Substituted 5-aryl-benzothiepines having activity as inhibitors of ileal bile acid transport and taurocholate uptake

ABSTRACT

Provided are novel benzothiepines, derivatives, and analogs thereof; pharmaceutical compositions containing them; and methods of using these compounds and compositions in medicine, particularly in the prophylaxis and treatment of hyperlipidemic conditions such as those associated with atherosclerosis or hypercholesterolemia, in mammals.

This application is a continuation-in-part application of U.S. application Ser. No. 09/109,551, filed Jul. 2, 1998, which is a continuation-in-part application of U.S. application Ser. No. 08/816,065, filed Mar. 11, 1997, now abandoned, which claims the benefit of priority of U.S. Provisional Application Ser. Nos. 60/013,119 and 60/068,170, filed Mar. 11, 1996, and Dec. 19, 1997, respectively. This application is also a continuation-in-part application of U.S. application Ser. No. 08/831,284, filed Mar. 31, 1997, now abandoned, which is a continuation of U.S. application Ser. No. 08/517,051, filed Aug. 21, 1995, now abandoned, which is a continuation-in-part application of U.S. application Ser. No. 08/305,526, filed Sep. 12, 1994, now abandoned.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to novel benzothiepines, derivatives and analogs thereof, pharmaceutical compositions containing them, and their use in medicine, particularly in the prophylaxis and treatment of hyperlipidemic conditions such as is associated with atherosclerosis or hypercholesterolemia, in mammals.

2. Description of Related Art

It is well-settled that hyperlipidemic conditions associated with elevated concentrations of total cholesterol and low-density lipoprotein cholesterol are major risk factors for coronary heart disease and particularly atherosclerosis. Interfering with the circulation of bile acids within the lumen of the intestinal tract is found to reduce the levels of serum cholesterol in a causal relationship. Epidemiological data has accumulated which indicates such reduction leads to an improvement in the disease state of atherosclerosis. Stedronsky, in "Interaction of bile acids and cholesterol with nonsystemic agents having hypocholesterolemic properties," Biochimica et Biophysica Acta, 1210 (1994) 255-287 discusses the biochemistry, physiology and known active agents surrounding bile acids and cholesterol.

Pathophysiologic alterations are shown to be consistent with interruption of the enterohepatic circulation of bile acids in humans by Heubi, J. E., et al. See "Primary Bile Acid Malabsorption: Defective in Vitro Ileal Active Bile Acid Transport", Gastroenterology, 1982:83:804-11.

In fact, cholestyramine binds the bile acids in the intestinal tract, thereby interfering with their normal enterohepatic circulation (Reihner, E. et al, in "Regulation of hepatic cholesterol metabolism in humans: stimulatory effects of cholestyramine on HMG-CoA reductase activity and low density lipoprotein receptor expression in gallstone patients", Journal of Lipid Research, Volume 31, 1990, 2219-2226 and Suckling el al, "Cholesterol Lowering and bile acid excretion in the hamster with cholestyramine treatment", Atherosclerosis, 89(1991) 183-190). This results in an increase in liver bile acid synthesis by the liver using cholesterol as well as an upregulation of the liver LDL receptors which enhances clearance of cholesterol and decreases serum LDL cholesterol levels.

In another approach to the reduction of recirculation of bile acids, the ileal bile acid transport system is a putative pharmaceutical target for the treatment of hypercholesterolemia based on an interruption of the enterohepatic circulation with specific transport inhibitors (Kramer, et al, "Intestinal Bile Acid Absorption" The Journal of Biological Chemistry, Vol. 268, No. 24, Issue of August 25, pp. 18035-18046, 1993).

In a series of patent applications, eg Canadian Patent Application Nos. 2,025,294; 2,078,588; 2,085,782; and 2,085,830; and EP Application Nos. 0 379 161; 0 549 967; 0 559 064; and 0 563 731, Hoechst Aktiengesellschaft discloses polymers of various naturally occurring constituents of the enterohepatic circulation system and their derivatives, including bile acid, which inhibit the physiological bile acid transport with the goal of reducing the LDL cholesterol level sufficiently to be effective as pharmaceuticals and, in particular for use as hypocholesterolemic agents.

In vitro bile acid transportinhibition is disclosed to show hypolipidemic activity in The Wellcome Foundation Limited disclosure of the world patent application number WO 93/16055 for "Hypolipidemic Benzothiazepine Compounds"

Selected benzothiepines are disclosed in world patent application number WO93/321146 for numerous uses including fatty acid metabolism and coronary vascular diseases.

Other selected benzothiepines are known for use as hypolipaemic and hypocholesterolaemic agents, especially for the treatment or prevention of atherosclerosis as disclosed by application Nos. EP 508425, FR 2661676, and WO 92/18462, each of which is limited by an amide bonded to the carbon adjacent the phenyl ring of the fused bicyclo benzothiepine ring.

The above references show continuing efforts to find safe, effective agents for the prophylaxis and treatment of hyperlipidemic diseases and their usefulness as hypocholesterolemic agents.

Additionally selected benzothiepines are disclosed for use in various disease states not within the present invention utility. These are EP 568 898A as abstracted by Derwent Abstract No. 93-351589; WO 89/1477/A as abstracted in Derwent Abstract No. 89-370688; U.S. Pat. No. 3,520,891 abstracted in Derwent 50701R-B; U.S. Pat. Nos. 3,287,370, 3,389,144; 3,694,446 abstracted in Derwent Abstr. No. 65860T-B and WO 92/18462.

The present invention furthers such efforts by providing novel benzothiepines, pharmaceutical compositions, and methods of use therefor.

SUMMARY OF THE INVENTION

Accordingly, among its various apects, the present invention provides compounds of formula (I): ##STR1## wherein: q is an integer from 1 to 4;

n is an integer from 0 to 2;

R¹ and R² are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, haloalkyl, alkylaryl, arylalkyl, alkoxy, alkoxyalkyl, dialkylamino, alkylthio, (polyalkyl)aryl, and cycloalkyl,

wherein alkyl, alkenyl, alkynyl, haloalkyl, alkylaryl, arylalkyl, alkoxy, alkoxyalkyl, dialkylamino, alkylthio, (polyalkyl)aryl, and cycloalkyl optionally are substituted with one or more substituents selected from the group consisting of OR⁹, NR⁹ R¹⁰, N⁺ R⁹ R¹⁰ R^(w) A⁻, SR⁹, S⁺ R⁹ R¹⁰ A⁻. P⁺ R⁹ R¹⁰ R¹¹ A⁻, S(O)R⁹, SO₂ R⁹, SO₃ R⁹, CO₂ R⁹, CN, halogen, oxo, and CONR⁹ R¹⁰,

wherein alkyl, alkenyl, alkynyl, alkylaryl, alkoxy, alkoxyalkyl, (polyalkyl)aryl, and cycloalkyl optionally have one or more carbons replaced by O, NR⁹, N⁺ R⁹ R¹⁰ A-, S, SO, SO₂, S⁺ R⁹ A⁻, P⁺ P⁹ R¹⁰ A⁻, or phenylene,

wherein R⁹, R¹⁰, and R^(w) are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, acyl, heterocycle, ammoniumalkyl, arylalkyl, carboxyalkyl, carboxyheteroaryl, carboxyheterocycle, carboalkoxyalkyl, carboxyalkylamino, heteroarylalkyl, heterocyclylalkyl, and alkylammoniumalkyl; or

R¹ and R² taken together with the carbon to which they are attached form C₃ -C₁₀ cycloalkyl;

R³ and R⁴ are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, acyloxy, aryl, heterocycle, OR⁹, NR⁹ R¹⁰, SR⁹, S(O)R⁹, SO₂ R⁹, and SO₃ R⁹, wherein R⁹ and R¹⁰ are as defined above; or

R³ and R⁴ together form ═O, ═NOR¹¹, ═S, ═NNR¹¹ R¹², ═NR⁹, or ═CR¹¹ R¹²,

wherein R¹¹ and R¹² are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkenylalkyl, alkynylalkyl, heterocycle, carboxyalkyl, carboalkoxyalkyl, cycloalkyl, cyanoalkyl, OR⁹, NR⁹ R¹⁰, SR⁹, S(O)R⁹, SO₂ R⁹, SO₃ R⁹, CO₂ R⁹, CN, halogen, oxo, and CONR⁹ R¹⁰, wherein R⁹ and R¹⁰ are as defined above, provided that both R³ and R⁴ cannot be OH, NH₂, and SH, or

R¹¹ and R¹² together with the nitrogen or carbon atom to which they are attached form a cyclic ring;

R⁵ and R⁶ are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, quaternary heterocycle, OR⁹, SR⁹, S(O)R⁹, SO₂ R⁹, and SO₃ R⁹,

wherein alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, quaternary heterocycle, and quaternary heteroaryl can be substituted with one or more substituent groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle, arylalkyl, quaternary heterocycle, quaternary heteroaryl, halogen, oxo, OR¹³, NR¹³ R¹⁴, SR¹³, S(O)R¹³, SO₂ R¹³, SO₃ R¹³, NR¹³ OR¹⁴, NR¹³ NR¹⁴ R¹⁵, NO₂, CO₂ R¹³, CN, OM, SO₂ OM, SO₂ NR¹³ R¹⁴, C(O)NR¹³ R¹⁴, C(O)OM, COR¹³, NR¹³ C(O)R¹⁴, NR¹³ C(O)NR¹⁴ R¹⁵, NR¹³ CO₂ R¹⁴, OC(O)R¹³, OC(O)NR¹³ R¹⁴, NR¹³ SOR¹⁴, NR¹³ SO₂ R¹⁴, NR¹³ SONR¹⁴ R¹⁵, NR¹³ SO₂ NR¹⁴ R¹⁵, P(O)R¹³ R¹⁴, P⁺ R¹³ R¹⁴ R¹⁵ A⁻, P(OR¹³)OR¹⁴, S⁺ R¹³ R¹⁴ A⁻, and N⁺ R⁹ R¹¹ R¹² A⁻,

wherein:

A⁻ is a pharmaceutically acceptable anion and M is a pharmaceutically acceptable cation,

said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, and heterocycle can be further substituted with one or more substituent groups selected from the group consisting of OR⁷, NR⁷ R⁸, SR⁷, S(O)R⁷, SO₂ R⁷, SO₃ R⁷, CO₂ R⁷, CN, oxo, CONR⁷ R⁸, N⁺ R⁷ R⁸ R⁹ A-, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, arylalkyl, quaternary heterocycle, quaternary heteroaryl, P(O)R⁷ R⁸, P⁺ R⁷ R⁸ R⁹ A⁻, and P(O)(OR⁷)OR⁸, and

wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, and heterocycle can optionally have one or more carbons replaced by O, NR⁷, N⁺ R⁷ R⁸ A-, S, SO, SO₂, S⁺ R⁷ A-, PR⁷, P(O)R⁷, P⁺ R⁷ R⁸ A-, or phenylene, and R¹³, R¹⁴, and R¹⁵ are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, arylalkyl, alkylarylalkyl, alkylheteroarylalkyl, alkylheterocyclylalkyl, cycloalkyl, heterocycle, heteroaryl, quaternary heterocycle, quaternary heteroaryl, heterocyclylalkyl, heteroarylalkyl, quaternary heterocyclylalkyl, quaternary heteroarylalkyl, alkylammoniumalkyl, and carboxyalkylaminocarbonylalkyl,

wherein alkyl, alkenyl, alkynyl, arylalkyl, heterocycle, and polyalkyl optionally have one or more carbons replaced by O, NR⁹, N⁺ R⁹ R¹⁰ A-, S, SO, SO₂, S⁺ R⁹ A⁻, PR⁹, P⁺ R⁹ R¹⁰ A-, P(O)R⁹, phenylene, carbohydrate, amino acid, peptide, or polypeptide, and

R¹³, R¹⁴, and R¹⁵ are optionally substituted with one or more groups selected from the group consisting of hydroxy, amino, sulfo, carboxy, alkyl, carboxyalkyl, heterocycle, heteroaryl, sulfoalkyl, quaternary heterocycle, quaternary heteroaryl, quaternary heterocyclylalkyl, quaternary heteroarylalkyl, guanidinyl, OR⁹, NR⁹ R¹⁰, N⁺ R⁹ R¹¹ R¹² A⁻, SR⁹, S(O)R⁹, SO₂ R⁹, SO₃ R⁹, oxo, CO₂ R⁹, CN, halogen, CONR⁹ R¹⁰, SO₂ OM, SO₂ NR⁹ R¹⁰, PO(OR¹⁶)OR¹⁷, P⁺ R⁹ R¹⁰ R¹¹ A-, S⁺ R⁹ R¹⁰ A-, and C(O)OM,

wherein R¹⁶ and R¹⁷ are independently selected from the substituents constituting R⁹ and M; or

R¹³ and R¹⁴, together with the nitrogen atom to which they are attached form a mono- or polycyclic heterocycle that is optionally substituted with one or more radicals selected from the group consisting of oxo, carboxy and quaternary salts; or

R¹⁴ and R¹⁵ together with the nitrogen atom to which they are attached, form a cyclic ring; and

R⁷ and R⁸ are independently selected from the group consisting of hydrogen and alkyl; and

one or more R^(x) are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, polyalkyl, acyloxy, aryl, arylalkyl, halogen, haloalkyl, cycloalkyl, heterocycle, heteroaryl, polyether, quaternary heterocycle, quaternary heteroaryl, OR¹³, NR¹³ R¹⁴, SR¹³, S(O)R¹³, S(O)₂ R¹³, SO₃ R¹³, S⁺ R¹³ R¹⁴ A-, NR¹³ OR¹⁴, NR¹³ NR¹⁴ R¹⁵, NO₂, CO₂ R¹³, CN, OM, SO₂ OM, SO₂ NR¹³ R¹⁴, NR¹⁴ C(O)R¹³, C(O)NR¹³ R¹⁴, NR¹⁴ C(O)R¹³, C(O)OM, COR¹³, OR¹⁸, S(O)_(n) NR¹⁸, NR¹³ R¹⁸, NR¹⁸ OR¹⁴, N⁺ R⁹ R¹¹ R¹² A⁻, P⁺ R⁹ R¹¹ R¹² A⁻, amino acid, peptide, polypeptide, and carbohydrate,

wherein alkyl, alkenyl, alkynyl, cycloalkyl, aryl, polyalkyl, heterocycle, acyloxy, arylalkyl, haloalkyl, polyether, quaternary heterocycle, and quaternary heteroaryl can be further substituted with OR⁹, NR⁹ R¹⁰, N⁺ R⁹ R¹¹ R¹² A⁻, SR⁹, S(O)R⁹, SO₂ R⁹, SO₃ R⁹, oxo, CO₂ R⁹, CN, halogen, CONR⁹ R¹⁰, SO₂ OM, SO₂ NR⁹ R¹⁰, PO(OR¹⁶)OR¹⁷, P⁺ R⁹ R¹¹ R¹² A⁻, S⁺ R⁹ R¹⁰ A⁻, or C(O)OM, and

wherein R¹⁸ is selected from the group consisting of acyl, arylalkoxycarbonyl, arylalkyl, heterocycle, heteroaryl, alkyl,

wherein acyl, arylalkoxycarbonyl, arylalkyl, heterocycle, heteroaryl, alkyl, quaternary heterocycle, and quaternary heteroaryl optionally are substituted with one or more substituents selected from the group consisting of OR⁹, NR⁹ R¹⁰, N⁺ R⁹ R¹¹ R¹² A⁻, SR⁹, S(O)R⁹, SO₂ R⁹, SO₃ R⁹, oxo, CO₂ R⁹, CN, halogen, CONR⁹ R¹⁰, SO₃ R⁹, SO₂ OM, SO₂ NR⁹ R¹⁰, PO(OR¹⁶)OR¹⁷, and C(O)OM,

wherein in R^(x), one or more carbons are optionally replaced by O, NR¹³, N⁺ R¹³ R¹⁴ A-, S, SO, SO₂, S⁺ R¹³ A⁻, PR¹³, P(O)R¹³, P⁺ R¹³ R¹⁴ A-, phenylene, amino acid, peptide, polypeptide, carbohydrate, polyether, or polyalkyl,

wherein in said polyalkyl, phenylene, amino acid, peptide, polypeptide, and carbohydrate, one or more carbons are optionally replaced by O, NR⁹, N⁺ R⁹ R¹⁰ A⁻, S, SO, SO₂, S⁺ R⁹ A-, PR⁹, P⁺ R⁹ R¹⁰ A-, or P(O)R⁹ ;

wherein quaternary heterocycle and quaternary heteroaryl are optionally substituted with one or more groups selected from the group consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle, arylalkyl, halogen, oxo, OR¹³, NR¹³ R¹⁴, SR¹³, S(O)R¹³, SO₂ R¹³, SO₃ R¹³, NR¹³ OR¹⁴, NR¹³ NR¹⁴ R¹⁵, NO₂, CO₂ R¹³, CN, OM, SO₂ OM, SO₂ NR¹³ R¹⁴, C(O)NR¹³ R¹⁴, C(O)OM, COR¹³, P(O)R¹³ R¹⁴, P⁺ R¹³ R¹⁴ R¹⁵ A⁻, P(OR¹³)OR¹⁴, S⁺ R¹³ R¹⁴ A⁻, and N⁺ R⁹ R¹¹ R¹² A⁻,

provided that both R⁵ and R⁶ cannot be hydrogen, OH, or SH and when R⁵ is OH, R¹, R², R³, R⁴, R⁷ and R⁸ cannot be all hydrogen;

provided that when R⁵ or R⁶ is phenyl, only one of R¹ or R² is H;

provided that when q=1 and R^(x) is styryl, anilido, or anilinocarbonyl, only one of R⁵ or R⁶ is alkyl;

provided that when n is 1, R¹, R³, R⁷, and R⁸ are hydrogen, R² is hydrogen, alkyl or aryl, R⁴ is unsubstituted amino or amino substituted with one or more alkyl or aryl radicals, and R⁵ is hydrogen, alkyl or aryl, then R⁶ is other than hydroxy; or

a pharmaceutically acceptable salt, solvate, or prodrug thereof.

Preferably, R⁵ and R⁶ can independently be selected from the group consisting of H, aryl, heterocycle, quaternary heterocycle, and quaternary heteroaryl,

wherein said aryl, heteroaryl, quaternary heterocycle, and quaternary heteroaryl can be substituted with one or more substituent groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle, arylalkyl, halogen, oxo, OR¹³, NR¹³ R¹⁴, SR¹³, S(O)R¹³, SO₂ R¹³, SO₃ R¹³, NR¹³ OR¹⁴, NR¹³ NR¹⁴ R¹⁵, NO₂, CO₂ R¹³, CN, OM, SO₂ OM, SO₂ NR¹³ R¹⁴, C(O)NR¹³ R¹⁴, C(O)OM, COR¹³, NR¹³ C(O)R¹⁴, NR¹³ C(O)NR¹⁴ R¹⁵, NR¹³ CO₂ R¹⁴, OC(O)R¹³, OC(O)NR¹³ R¹⁴, NR¹³ SOR¹⁴, NR¹³ SO₂ R¹⁴, NR¹³ SONR¹⁴ R¹⁵, NR¹³ SO₂ NR¹⁴ R¹⁵, P(O)R¹³ R¹⁴, P⁺ R¹³ R¹⁴ R¹⁵ A-, P(OR¹³)OR¹⁴, S+R¹³ R¹⁴ A-, and N⁺ R⁹ R¹¹ R¹² A⁻,

wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, and heterocycle can optionally have one or more carbons replaced by O, NR⁷, N⁺ R⁷ R⁸ A-, S, SO, SO₂, S⁺ R⁷ A-, PR⁷, P(O)R⁷, P⁺ R⁷ R⁸ A-, or phenylene,

wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, and heterocycle can be further substituted with one or more substituent groups selected from the group consisting of OR⁷, NR⁷ R⁸, SR⁷, S(O)R⁷, SO₂ R⁷, SO₃ R⁷, CO₂ R⁷, CN, oxo, CONR⁷ R⁸, N⁺ R⁷ R⁸ R⁹ A⁻, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, arylalkyl, quaternary heterocycle, quaternary heteroaryl, P(O)R⁷ R⁸, P⁺ R⁷ R⁸ A⁻, and P(O)(OR⁷)OR⁸.

More preferably, R⁵ or R⁶ has the formula:

    --Ar--(R.sup.y).sub.t

wherein:

t is an integer from 0 to 5;

Ar is selected from the group consisting of phenyl, thiophenyl, pyridyl, piperazinyl, piperonyl, pyrrolyl, naphthyl, furanyl, anthracenyl, quinolinyl, isoquinolinyl, quinoxalinyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, pyrimidinyl, thiazolyl, triazolyl, isothiazolyl, indolyl, benzoimidazolyl, benzoxazolyl, benzothiazolyl, and benzoisothiazolyl; and

one or more R_(y) are independently selected from the group consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle, arylalkyl, halogen, oxo, OR¹³, NR¹³ R¹⁴, SR¹³, S(O)R¹³, SO₂ R¹³, SO₃ R¹³, NR¹³ OR¹⁴, NR¹³ NR¹⁴ R¹⁵, NO₂, CO₂ R¹³, CN, OM, SO₂ OM, SO₂ NR¹³ R¹⁴, C(O)NR¹³ R¹⁴, C(O)OM, COR¹³, NR¹³ C(O)R¹⁴, NR¹³ C(O)NR¹⁴ R¹⁵, NR¹³ CO₂ R¹⁴, OC(O)R¹³, OC(O)NR¹³ R¹⁴, NR¹³ SOR¹⁴, NR¹³ SO₂ R¹⁴, NR¹³ SONR¹⁴ R¹⁵, NR¹³ SO₂ NR¹⁴ R¹⁵, P(O)R¹³ R¹⁴, P⁺ R¹³ R¹⁴ R¹⁵ A⁻, P(OR¹³)OR¹⁴, S⁺ R¹³ R¹⁴ A⁻, and N⁺ R⁹ R¹¹ R¹² A⁻,

wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, and heterocycle can be further substituted with one or more substituent groups selected from the group consisting of OR⁷, NR⁷ R⁸, SR⁷, S(O)R⁷, SO₂ R⁷, SO₃ R⁷, CO₂ R⁷, CN, oxo, CONR⁷ R⁸, N⁺ R⁷ R⁸ R⁹ A-, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, arylalkyl, quaternary heterocycle, quaternary heteroaryl, P(O)R⁷ R⁸, P⁺ R⁷ R⁸ A⁻, and P(O)(OR⁷)OR⁸, and

wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, and heterocycle can optionally have one or more carbons replaced by O, NR⁷, N⁺ R⁷ R⁸ A-, S, SO, SO₂, S⁺ R⁷ A-, PR⁷, P(O)R⁷, P⁺ R⁷ R⁸ A-, or phenylene.

Most preferably, R⁵ or R⁶ has the formula (II): ##STR2##

Another embodiment of the invention is further directed to compounds of Formula I wherein at least one or more of the following conditions exist:

(1) R¹ and R² are independently selected from the group consisting of hydrogen and alkyl. Preferably, R¹ and R² are independently selected from the group consisting of C₁₋₆ alkyl. More preferably, R¹ and R² are the same C₁₋₆ alkyl. Still more preferably, R¹ and R² are n-butyl; and/or

(2) R³ and R⁴ are independently selected from the group consisting of hydrogen and OR⁹ wherein R⁹ is defined as set forth above. Preferably, R³ is hydrogen and R⁴ is OR⁹. Still more preferably, R³ is hydrogen and R⁴ is hydroxy; and/or

(3) R⁵ is substituted aryl. Preferably, R⁵ is substituted phenyl. More preferably, R⁵ is phenyl substituted with a radical selected from the group consisting of OR¹³, NR¹³ C(O)R¹⁴, NR¹³ C(O)NR¹⁴ R¹⁵, NR¹³ CO₂ R¹⁴, OC(O)R¹³, OC(O)NR¹³ R¹⁴, NR¹³ SOR¹⁴, NR¹³ SO₂ R¹⁴, NR¹³ SONR¹⁴ R¹⁵, and NR¹³ SO₂ NR¹⁴ R¹⁵ wherein R¹³, R¹⁴ and R¹⁵ are as set forth above. Still more preferably, R⁵ is phenyl substituted with OR¹³. Still more preferably, R⁵ is phenyl substituted at the para or meta position with OR¹³ wherein R¹³ comprises a quaternary heterocycle, quaternary heteroaryl or substituted amino; and/or

(4) R⁶ is hydrogen; and/or

(5) R⁷ and R⁸ are independently selected from the group consisting of hydrogen and alkyl. Preferably, R¹ and R² are independently selected from the group C₁₋₆ alkyl. Still more preferably, R¹ and R² are hydrogen; and/or

(6) R^(x) is selected from the group consisting of OR¹³ and NR¹³ R¹⁴. Preferably, R^(x) is selected from the group consisting of alkoxy, amino, alkylamino and dialkylamino. Still more preferably, R^(x) is selected from the group consisting of methoxy and dimethylamino.

Another embodiment of the invention is further directed to compounds of formula 1: ##STR3## wherein: q is an integer from 1 to 4;

n is an integer from 0 to 2;

R¹ and R² are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, haloalkyl, alkylaryl, arylalkyl, alkoxy, alkoxyalkyl, dialkylamino, alkylthio, (polyalkyl)aryl, and cycloalkyl,

wherein alkyl, alkenyl, alkynyl, haloalkyl, alkylaryl, arylalkyl, alkoxy, alkoxyalkyl, dialkylamino, alkylthio, (polyalkyl)aryl, and cycloalkyl optionally are substituted with one or more substituents selected from the group consisting of OR⁹, NR⁹ R¹⁰, N⁺ R⁹ R¹⁰ R^(w) A⁻, SR⁹, S⁺ R⁹ R¹⁰ A⁻. P⁺ R⁹ R¹⁰ R¹¹ A⁻, S(O)R⁹, SO₂ R⁹, SO₃ R⁹, CO₂ R⁹, CN, halogen, oxo, and CONR⁹ R¹⁰,

wherein alkyl, alkenyl, alkynyl, alkylaryl, alkoxy, alkoxyalkyl, (polyalkyl)aryl, and cycloalkyl optionally have one or more carbons replaced by O, NR⁹, N⁺ R⁹ R¹⁰ A-, S, SO, SO₂, S⁺ R⁹ A⁻, P⁺ R⁹ R¹⁰ A⁻, or phenylene,

wherein R⁹, R¹⁰, and R^(w) are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, acyl, heterocycle, ammoniumalkyl, arylalkyl, carboxyalkyl, carboxyheteroaryl, carboxyheterocycle, carboalkoxyalkyl, carboxyalkylamino, heteroarylalkyl, heterocyclylalkyl, and alkylammoniumalkyl; or

R¹ and R² taken together with the carbon to which they are attached form C₃ -C₁₀ cycloalkyl;

R³ and R⁴ are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, acyloxy, aryl, heterocycle, OR⁹, SR⁹, S(O)R⁹, SO₂ R⁹, and SO₃ R⁹, wherein R⁹ and R¹⁰ are as defined above; or

R³ and R⁴ together form ═O, ═NOR¹¹, ═S, ═NNR¹¹ R¹², ═NR⁹, or ═CR¹¹ R¹²,

wherein R¹¹ and R¹² are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkenylalkyl, alkynylalkyl, heterocycle, carboxyalkyl, carboalkoxyalkyl, cycloalkyl, cyanoalkyl, OR⁹, NR⁹ R¹⁰, SR⁹, S(O)R⁹, SO₂ R⁹, SO₃ R⁹, CO₂ R⁹, CN, halogen, oxo, and CONR⁹ R¹⁰, wherein R⁹ and R¹⁰ are as defined above, provided that both R³ and R⁴ cannot be OH, NH₂, and SH, or

R¹¹ and R¹² together with the nitrogen or carbon atom to which they are attached form a cyclic ring;

R⁵ is selected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, quaternary heterocycle, OR⁹, SR⁹, S(O)R⁹, SO₂ R⁹, and SO₃ R⁹,

wherein alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, quaternary heterocycle, and quaternary heteroaryl can be substituted with one or more substituent groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle, arylalkyl, quaternary heterocycle, quaternary heteroaryl, halogen, oxo, OR¹³, NR¹³ R¹⁴, SR¹³, S(O)R¹³, SO₂ R¹³, SO₃ R¹³, NR¹³ OR¹⁴, NR¹³ NR¹⁴ R¹⁵, NO₂, CO₂ R¹³, CN, OM, SO₂ OM, SO₂ NR¹³ R¹⁴, C(O)NR¹³ R¹⁴, C(O)OM, COR¹³, NR¹³ C(O)R¹⁴, NR¹³ C(O)NR¹⁴ R¹⁵, NR¹³ CO₂ R¹⁴, OC(O)R¹³, OC(O)NR¹³ R¹⁴, NR¹³ SOR¹⁴, NR¹³ SO₂ R¹⁴, NR¹³ SONR¹⁴ R¹⁵, NR¹³ SO₂ NR¹⁴ R¹⁵, P(O)R¹³ R¹⁴, P⁺ R¹³ R¹⁴ R¹⁵ A⁻, P(OR¹³)OR¹⁴, S⁺ R¹³ R¹⁴ A⁻, and N⁺ R⁹ R¹¹ R¹² A⁻,

wherein:

A⁻ is a pharmaceutically acceptable anion and M is a pharmaceutically acceptable cation,

said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, and heterocycle can be further substituted with one or more substituent groups selected from the group consisting of OR⁷, NR⁷ R⁸, SR⁷, S(O)R⁷, SO₂ R⁷, SO₃ R⁷, CO₂ R⁷, CN, oxo, CONR⁷ R⁸, N⁺ R⁷ R⁸ R⁹ A-, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, arylalkyl, quaternary heterocycle, quaternary heteroaryl, P(O)R⁷ R⁸, P⁺ R⁷ R⁸ R⁹ A⁻, and P(O)(OR⁷)OR⁸, and

wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, and heterocycle can optionally have one or more carbons replaced by O, NR⁷, N⁺ R⁷ R⁸ A-, S, SO, SO₂, S⁺ R⁷ A-, PR⁷, P(O)R⁷, P⁺ R⁷ R⁸ A-, or phenylene, and R¹³, R¹⁴, and R¹⁵ are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, arylalkyl, alkylarylalkyl, alkylheteroarylalkyl, alkylheterocyclylalkyl, cycloalkyl, heterocycle, heteroaryl, quaternary heterocycle, quaternary heteroaryl, heterocyclylalkyl, heteroarylalkyl, quaternary heterocyclylalkyl, quaternary heteroarylalkyl, alkylammoniumalkyl, and carboxyalkylaminocarbonylalkyl,

wherein alkyl, alkenyl, alkynyl, arylalkyl, heterocycle, and polyalkyl optionally have one or more carbons replaced by O, NR⁹, N⁺ R⁹ R¹⁰ A-, S, SO, SO₂, S⁺ R⁹ A⁻, PR⁹, P⁺ R⁹ R¹⁰ A-, P(O)R⁹, phenylene, carbohydrate, amino acid, peptide, or polypeptide, and

R¹³, R¹⁴, and R¹⁵ are optionally substituted with one or more groups selected from the group consisting of hydroxy, amino, sulfo, carboxy, alkyl, carboxyalkyl, heterocycle, heteroaryl, sulfoalkyl, quaternary heterocycle, quaternary heteroaryl, quaternary heterocyclylalkyl, quaternary heteroarylalkyl, guanidinyl, OR⁹, NR⁹ R¹⁰, N⁺ R⁹ R¹¹ R¹² A⁻, SR⁹, S(O)R⁹, SO₂ R⁹, SO₃ R⁹, oxo, CO₂ R⁹, CN, halogen, CONR⁹ R¹⁰, SO₂ OM, SO₂ NR⁹ R¹⁰, PO(OR¹⁶)OR¹⁷, P⁺ R⁹ R¹⁰ R¹¹ A-, S⁺ R⁹ R¹⁰ A-, and C(O)OM,

wherein R¹⁶ and R¹⁷ are independently selected from the substituents constituting R⁹ and M; or

R¹³ and R¹⁴, together with the nitrogen atom to which they are attached form a mono- or polycyclic heterocycle that is optionally substituted with one or more radicals selected from the group consisting of oxo, carboxy and quaternary salts; or

R¹⁴ and R¹⁵, together with the nitrogen atom to which they are attached, form a cyclic ring; and

R⁶ is hydroxy; and

R⁷ and R⁸ are independently selected from the group consisting of hydrogen and alkyl; and

one or more R^(x) are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, polyalkyl, acyloxy, aryl, arylalkyl, halogen, haloalkyl, cycloalkyl, heterocycle, heteroaryl, polyether, quaternary heterocycle, quaternary heteroaryl, OR¹³, NR¹³ R¹⁴, SR¹³, S(O)R¹³, S(O)₂ R¹³, SO₃ R¹³, S⁺ R¹³ R¹⁴ A-, NR¹³ OR¹⁴, NR¹³ NR¹⁴ R¹⁵, NO₂, CO₂ R¹³, CN, OM, SO₂ OM, SO₂ NR¹³ R¹⁴, NR¹⁴ C(O)R¹³, C(O)NR¹³ R¹⁴, NR¹⁴ C(O)R¹³, C(O)OM, COR¹³, OR¹⁸, S(O)_(n) NR¹⁸, NR¹³ R¹⁸, NR¹⁸ OR¹⁴, N⁺ R⁹ R¹¹ R¹² A⁻, P⁺ R⁹ R¹¹ R¹² A⁻, amino acid peptide, polypeptide, and carbohydrate,

wherein alkyl, alkenyl, alkynyl, cycloalkyl, aryl, polyalkyl, heterocycle, acyloxy, arylalkyl, haloalkyl, polyether, quaternary heterocycle, and quaternary heteroaryl can be further substituted with OR⁹, NR⁹ R¹⁰, N⁺ R⁹ R¹¹ R¹² A⁻, SR⁹, S(O)R⁹, SO₂ R⁹, SO₃ R⁹, oxo, CO₂ R⁹, CN, halogen, CONR⁹ R¹⁰, SO₂ OM, SO₂ NR⁹ R¹⁰, PO(OR¹⁶)OR¹⁷, P⁺ R⁹ R¹¹ R¹² A⁻, S⁺ R⁹ R¹⁰ A⁻, or C(O)OM, and

wherein R¹⁸ is selected from the group consisting of acyl, arylalkoxycarbonyl, arylalkyl, heterocycle, heteroaryl, alkyl,

wherein acyl, arylalkoxycarbonyl, arylalkyl, heterocycle, heteroaryl, alkyl, quaternary heterocycle, and quaternary heteroaryl optionally are substituted with one or more substituents selected from the group consisting of OR⁹, NR⁹ R¹⁰, N⁺ R⁹ R¹¹ R¹² A⁻, SR⁹, S(O)R⁹, SO₂ R⁹, SO₃ R⁹, oxo, CO₂ R⁹, CN, halogen, CONR⁹ R¹⁰, SO₃ R⁹, SO₂ OM, SO₂ NR⁹ R¹⁰, PO(OR¹⁶)OR¹⁷, and C(O)OM,

wherein in R^(x), one or more carbons are optionally replaced by O, NR¹³, N⁺ R¹³ R¹⁴ A-, S, SO, SO₂, S⁺ R¹³ A⁻, PR¹³, P(O)R¹³, P⁺ R¹³ R¹⁴ A-, phenylene, amino acid, peptide, polypeptide, carbohydrate, polyether, or polyalkyl,

wherein in said polyalkyl, phenylene, amino acid, peptide, polypeptide, and carbohydrate, one or more carbons are optionally replaced by O, NR⁹, N⁺ R⁹ R¹⁰ A⁻, S, SO, SO₂, S⁺ R⁹ A-, PR⁹, P⁺ R⁹ R¹⁰ A-, or P(O)R⁹ ;

wherein quaternary heterocycle and quaternary heteroaryl are optionally substituted with one or more groups selected from the group consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle, arylalkyl, halogen, oxo, OR¹³, NR¹³ R¹⁴, SR¹³, S(O)R¹³, SO₂ R¹³, SO₃ R¹³, NR¹³ OR¹⁴, NR¹³ NR¹⁴ R¹⁵, NO₂, CO₂ R¹³, CN, OM, SO₂ OM, SO₂ NR¹³ R¹⁴, C(O)NR¹³ R¹⁴, C(O)OM, COR¹³, P(O)R¹³ R¹⁴, P⁺ R¹³ R¹⁴ R¹⁵ A⁻, P(OR¹³)OR¹⁴, S⁺ R¹³ R¹⁴ A⁻, and N⁺ R⁹ R¹¹ R¹² A⁻,

provided that both R⁵ and R⁶ cannot be hydrogen, OH, or SH;

provided that when R⁵ is phenyl, only one of R¹ or R² is H; or

a pharmaceutically acceptable salt, solvate, or prodrug thereof.

The invention is further directed to a compound selected from among: ##STR4## wherein R¹⁹ is selected from the group consisting of alkane diyl, alkene diyl, alkyne diyl, polyalkane diyl, alkoxy diyl, polyether diyl, polyalkoxy diyl, carbohydrate, amino acid, peptide, and polypeptide, wherein alkane diyl, alkene diyl, alkyne diyl, polyalkane diyl, alkoxy diyl, polyether diyl, polyalkoxy diyl, carbohydrate, amino acid, peptide, and polypeptide can optionally have one or more carbon atoms replaced by O, NR⁷, N⁺ R⁷ R⁸, S, SO, SO₂, S⁺ R⁷ R⁸, PR⁷, P⁺ R⁷ R⁸, phenylene, heterocycle, quatarnary heterocycle, quaternary heteroaryl, or aryl,

wherein alkane diyl, alkene diyl, alkyne diyl, polyalkane diyl, alkoxy diyl, polyether diyl, polyalkoxy diyl, carbohydrate, amino acid, peptide, and polypeptide can be substituted with one or more substituent groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle, arylalkyl, halogen, oxo, OR¹³, NR¹³ R¹⁴, SR¹³, S(O)R¹³, SO₂ R¹³, SO₃ R¹³, NR¹³ OR¹⁴, NR¹³ NR¹⁴ R¹⁵, NO₂, CO₂ R¹³, CN, OM, SO₂ OM, SO₂ NR¹³ R¹⁴, C(O)NR¹³ R¹⁴, C(O)OM, COR¹³, P(O)R⁻⁻ R¹⁴, P⁺ R¹³ R¹⁴ R15A-, P(OR¹³)OR¹⁴, S⁺ R¹³ R¹⁴ A⁻, and N⁺ R⁹ R¹¹ R¹² A⁻ ;

wherein R¹⁹ further comprises functional linkages by which R¹⁹ is bonded to R²⁰, R²¹, or R²² in the compounds of Formulae DII and DIII, and R²³ in the compounds of Formula DIII. Each of R²⁰, R²¹, or R²² and R²³ comprises a benzothiepine moiety as described above that is therapeutically effective in inhibiting ileal bile acid transport.

The invention is also directed to a compound selected from among Formula DI, Formula DII and Formula DIII in which each of R²⁰, R²¹, R²² and R²³ comprises a benzothiepine moiety corresponding to the Formula: ##STR5## wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R^(x), q, and n are as defined in Formula I as described above, and R⁵⁵ is either a covalent bond or arylene.

In compounds of Formula DIV, it is particularly preferred that each of R²⁰, R²¹, and R²² in Formulae DII and DIII, and R²³ in Formula DIII, be bonded at its 7- or 8-position to R¹⁹. In compounds of Formula DIVA, it is particularly preferred that p⁵⁵ comprise a phenylene moiety bonded at a m- or p-carbon thereof to R¹⁹.

Examples of Formula DI include: ##STR6##

In any of the dimeric or multimeric structures discussed immediately above, benzothiepine compounds of the present invention can be used alone or in various combinations.

In any of the compounds of the present invention, R¹ and R² can be ethyl/butyl or butyl/butyl.

In another aspect, the present invention provides a pharmaceutical composition for the prophylaxis or treatment of a disease or condition for which a bile acid transport inhibitor is indicated, such as a hyperlipidemic condition, for example, atherosclerosis. Such compositions comprise any of the compounds disclosed above, alone or in combination, in an amount effective to reduce bile acid levels in the blood, or to reduce transport thereof across digestive system membranes, and a pharmaceutically acceptable carrier, excipient, or diluent.

In a further aspect, the present invention also provides a method of treating a disease or condition in mammals, including humans, for which a bile acid transport inhibitor is indicated, comprising administering to a patient in need thereof a compound of the present invention in an effective amount in unit dosage form or in divided doses.

In yet a further aspect, the present invention also provides processes for the preparation of compounds of the present invention.

Further scope of the applicability of the present invention will become apparent from the detailed description provided below. However, it should be understood that the following detailed description and examples, while indicating preferred embodiments of the invention, are given by way of illustration only since various changes and modifications within the spirit and scope of the invention will become apparent to those skilled in the art from this detailed description.

DETAILED DESCRIPTION OF THE INVENTION

The following detailed description is provided to aid those skilled in the art in practicing the present invention. Even so, this detailed description should not be construed to unduly limit the present invention as modifications and variations in the embodiments discussed herein can be made by those of ordinary skill in the art without departing from the spirit or scope of the present inventive discovery.

The contents of each of the references cited herein, including the contents of the references cited within these primary references, are herein incorporated by reference in their entirety.

Definitions

In order to aid the reader in understanding the following detailed description, the following definitions are provided:

"Alkyl", "alkenyl," and "alkynyl" unless otherwise noted are each straight chain or branched chain hydrocarbons of from one to twenty carbons for alkyl or two to twenty carbons for alkenyl and alkynyl in the present invention and therefore mean, for example, methyl, ethyl, propyl, butyl, pentyl or hexyl and ethenyl, propenyl, butenyl, pentenyl, or hexenyl and ethynyl, propynyl, butynyl, pentynyl, or hexynyl respectively and isomers thereof.

"Aryl" means a fully unsaturated mono- or multi-ring carbocyle, including, but not limited to, substituted or unsubstituted phenyl, naphthyl, or anthracenyl.

"Heterocycle" means a saturated or unsaturated mono- or multi-ring carbocycle wherein one or more carbon atoms can be replaced by N, S, P, or O. This includes, for example, the following structures: ##STR7## wherein Z, Z', Z" or Z'" is C, S, P, O, or N, with the proviso that one of Z, Z', Z" or Z'" is other than carbon, but is not O or S when attached to another Z atom by a double bond or when attached to another O or S atom. Furthermore, the optional substituents are understood to be attached to Z, Z', Z" or Z'" only when each is C.

The term "heteroaryl" means a fully unsaturated heterocycle.

In either "heterocycle" or "heteroaryl," the point of attachment to the molecule of interest can be at the heteroatom or elsewhere within the ring.

The term "quaternary heterocycle" means a heterocycle in which one or more of the heteroatoms, for example, O, N, S, or P, has such a number of bonds that it is positively charged. The point of attachment of the quaternary heterocycle to the molecule of interest can be at a heteroatom or elsewhere.

The term "quaternary heteroaryl" means a heteroaryl in which one or more of the heteroatoms, for example, O, N, S, or P, has such a number of bonds that it is positively charged. The point of attachment of the quaternary heteryaryl to the molecule of interest can be at a heteroatom or elsewhere.

The term "halogen" means a fluoro, chloro, bromo or iodo group.

The term "haloalkyl" means alkyl substituted with one or more halogens.

The term "cycloalkyl" means a mono- or multi-ringed carbocycle wherein each ring contains three to ten carbon atoms, and wherein any ring can contain one or more double or triple bonds. Examples include radicals such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloalkenyl, and cycloheptyl. The term "cycloalkyl" additionally encompasses spiro systems wherein the cycloalkyl ring has a carbon ring atom in common with the seven-membered heterocyclic ring of the benzothiepine.

The term "diyl" means a diradical moiety wherein said moiety has two points of attachment to molecules of interest.

The term "oxo" means a doubly bonded oxygen.

The term "polyalkyl" means a branched or straight hydrocarbon chain having a molecular weight up to about 20,000, more preferably up to about 10,000, most preferably up to about 5,000.

The term "polyether" means a polyalkyl wherein one or more carbons are replaced by oxygen, wherein the polyether has a molecular weight up to about 20,000, more preferably up to about 10,000, most preferably up to about 5,000.

The term "polyalkoxy" means a polymer of alkylene oxides, wherein the polyalkoxy has a molecular weight up to about 20,000, more preferably up to about 10,000, most preferably up to about 5,000.

The term "cycloaklylidene" means a mono- or multi-ringed carbocycle wherein a carbon within the ring structure is doubly bonded to an atom which is not within the ring structures.

The term "carbohydrate" means a mono-, di-, tri-, or polysaccharide wherein the polysaccharide can have a molecular weight of up to about 20,000, for example, hydroxypropyl-methylcellulose or chitosan.

The term "peptide" means polyamino acid containing up to about 100 amino acid units.

The term "polypeptide" means polyamino acid containing from about 100 amino acid units to about 1000 amino acid units, more preferably from about 100 amino acid units to about 750 amino acid untis, most preferably from about 100 amino acid units to about 500 amino acid units.

The term "alkylammoniumalkyl" means a NH₂ group or a mono-, di- or tri-substituted amino group, any of which is bonded to an alkyl wherein said alkyl is bonded to the molecule of interest.

The term "triazolyl" includes all positional isomers. In all other heterocycles and heteroaryls which contain more than one ring heteroatom and for which isomers are possible, such isomers are included in the definition of said heterocycles and heteroaryls.

The term "sulfo" means a sulfo group, --SO₃ H, or its salts.

The term "sulfoalkyl" means an alkyl group to which a sulfonate group is bonded, wherein said alkyl is bonded to the molecule of interest.

The term "arylalkyl" means an aryl-substituted alkyl radical such as benzyl. The term "alkylarylalkyl" means an arylalkyl radical that is substituted on the aryl group with one or more alkyl groups.

The term "heterocyclylalkyl" means an alkyl radical that is substituted with one or more heterocycle groups. Preferable heterocyclylalkyl radicals are "lower heterocyclylalkyl" radicals having one or more heterocycle groups attached to an alkyl radical having one to ten carbon atoms.

The term "heteroarylalkyl" means an alkyl radical that is substituted with one or more heteroaryl groups. Preferable heteroarylalkyl radicals are "lower heteroarylalkyl" radicals having one or more heteroaryl groups attached to an alkyl radical having one to ten carbon atoms.

The term "quaternary heterocyclylalkyl" means an alkyl radical that is substituted with one or more quaternary heterocycle groups. Preferable quaternary heterocyclylalkyl radicals are "lower quaternary heterocyclylalkyl" radicals having one or more quaternary heterocycle groups attached to an alkyl radical having one to ten carbon atoms.

The term "quaternary heteroarylalkyl" means an alkyl radical that is substituted with one or more quaternary heteroaryl groups. Preferable quaternary heteroarylalkyl radicals are "lower quaternary heteroarylalkyl" radicals having one or more quaternary heteroaryl groups attached to an alkyl radical having one to ten carbon atoms.

The term "alkylheteroarylalkyl" means a heteroarylalkyl radical that is substituted with one or more alkyl groups. Preferable alkylheteroarylalkyl radicals are "lower alkylheteroarylalkyl" radicals with alkyl portions having one to ten carbon atoms.

The term "alkoxy" an alkyl radical which is attached to the remainder of the molecule by oxygen, such as a methoxy radical. More preferred alkoxy radicals are "lower alkoxy" radicals having one to six carbon atoms. Examples of such radicals include methoxy, ethoxy, propoxy, iso-propoxy, butoxy and tert-butoxy.

The term "carboxy" means the carboxy group, --CO₂ H, or its salts.

The term "carboxyalkyl" means an alkyl radical that is substituted with one or more carboxy groups. Preferable carboxyalkyl radicals are "lower carboxyalkyl" radicals having one or more carboxy groups attached to an alkyl radical having one to six carbon atoms.

The term "carboxyheterocycle" means a heterocycle radical that is substituted with one or more carboxy groups.

The term "carboxyheteroaryl" means a heteroaryl radical that is substituted with one or more carboxy groups.

The term "carboalkoxyalkyl" means an alkyl radical that is substituted with one or more alkoxycarbonyl groups. Preferable carboalkoxyalkyl radicals are "lower carboalkoxyalkyl" radicals having one or more alkoxycarbonyl groups attached to an alkyl radical having one to six carbon atoms.

The term "carboxyalkylamino" means an amino radical that is mono- or di-substituted with carboxyalkyl. Preferably, the carboxyalkyl substituent is a "lower carboxyalkyl" radical wherein the carboxy group is attached to an alkyl radical having one to six carbon atoms.

The term "active compound" means a compound of the present invention which inhibits transport of bile acids.

When used in combination, for example "alkylaryl" or "arylalkyl," the individual terms listed above have the meaning indicated above.

The term "a bile acid transport inhibitor" means a compound capable of inhibiting absorption of bile acids from the intestine into the circulatory system of a mammal, such as a human. This includes increasing the fecal excretion of bile acids, as well as reducing the blood plasma or serum concentrations of cholesterol and cholesterol ester, and more specifically, reducing LDL and VLDL cholesterol. Conditions or diseases which benefit from the prophylaxis or treatment by bile acid transport inhibition include, for example, a hyperlipidemic condition such as atherosclerosis.

Compounds

The compounds of the present invention can have at least two asymmetrical carbon atoms, and therefore include racemates and stereoisomers, such as diastereomers and enantiomers, in both pure form and in admixture. Such stereoisomers can be prepared using conventional techniques, either by reacting enantiomeric starting materials, or by separating isomers of compounds of the present invention.

Isomers may include geometric isomers, for example cis isomers or trans isomers across a double bond. All such isomers are contemplated among the compounds of the present invention.

The compounds of the present invention also include tautomers.

The compounds of the present invention as discussed below include their salts, solvates and prodrugs.

Compound Syntheses

The starting materials for use in the preparation of the compounds of the invention are known or can be prepared by conventional methods known to a skilled person or in an analogous manner to processes described in the art.

Generally, the compounds of the present invention can be prepared by the procedures described below.

For example, as shown in Scheme I, reaction of aldehyde II with formaldehyde and sodium hydroxide yields the hydroxyaldehyde III which is converted to mesylate IV with methansulfonyl chloride and triethylamine similar to the procedure described in Chem. Ber. 98, 728-734 (1965). Reaction of mesylate IV with thiophenol V, prepared by the procedure described in WO 93/16055, in the presence of triethylamine yields keto-aldehyde VI which can be cyclized with the reagent, prepared from zinc and titanium trichloride in refluxing ethylene glycol dimethyl ether (DME), to give a mixture of 2,3-dihydrobenzothiepine VII and two racemic steroisomers of benzothiepin-(5H)-4-one VIII when R¹ and R² are nonequivalent. Oxidation of VII with 3 equivalents of m-chloro-perbenzoic acid (MCPBA) gives isomeric sulfone-epoxides IX which upon hydrogenation with palladium on carbon as the catalyst yield a mixture of four racemic stereoisomers of 4-hydroxy-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxides X and two racemic stereoisomers of 2,3,4,5-tetrahydro-benzothiepine-1,1-dioxides XI when R¹ and R² are nonequivalent.

Optically active compounds of the present invention can be prepared by using optically active starting material III or by resolution of compounds X with optical resolution agents well known in the art as described in J. Org. Chem., 39, 3904 (1974), ibid., 42, 2781 (1977), and ibid., 44, 4891 (1979). ##STR8##

Alternatively, keto-aldehyde VI where R² is H can be prepared by reaction of thiophenol V with a 2-substituted acrolein. ##STR9##

Benzothiepin-(5H)-4-one VIII can be oxidized with MCPBA to give the benzothiepin-(5H)-4-one-1,1-dioxide XII which can be reduced with sodium borohydride to give four racemic stereoisomers of X. The two stereoisomers of X, Xa and Xb, having the OH group and R⁵ on the opposite sides of the benzothiepine ring can be converted to the other two isomers of X, Xc and Xd, having the OH group and R⁵ on the same side of the benzothiepine ring by reaction in methylene chloride with 40-50% sodium hydroxide in the presence of a phase transfer catalyst (PTC). The transformation can also be carried out with potassium t-butoxide in THF. ##STR10## MCPBA=m-chloroperbenzoic acid PTC=phase transfer catalyst

when R¹ =butyl, R² =ethyl, R⁵ =phenyl, X═H, q=4

6a=Xa

6b=Xb

6c=Xc

6d=Xd

The compounds of the present invention where R⁵ is OR, NRR' and S(O)_(n) R and R⁴ is hydroxy can be prepared by reaction of epoxide IX where R⁵ is H with thiol, alcohol, and amine in the presence of a base. ##STR11##

Another route to Xc and Xd of the present invention is shown in Scheme 2. Compound VI is oxidized to compound XIII with two equivalent of m-chloroperbenzoic acid. Hydrogenolysis of compound XIII with palladium on carbon yields compound XIV which can be cyclized with either potassium t-butoxide or sodium hydroxide under phase transfer conditions to a mixture of Xc and Xd. Separation of Xc and Xd can be accomplished by either HPLC or fractional crystallization.

The thiophenols XVIII and V used in the present invention can also be prepared according to the Scheme 3. Alkylation of phenol XV with an arylmethyl chloride in a nonpolar solvent according to the procedure in J. Chem. Soc., 2431-2432 (1958) gives the ortho substituted phenol XVI. The phenol XVI can be converted to the thiophenol XVIII via the thiocarbamate XVII by the procedure described in J. Org. Chem., 31, 3980 (1966). The phenol XVI is first reacted with dimethyl thiocarbamoyl chloride and triethylamine to give thiocarbamate XVII which is thermally rearranged at 200-300° C., and the rearranged product is hydrolyzed with sodium hydroxide to yield the thiophenol XVIII. Similarly, Thiophenol V can also be prepared from 2-acylphenol XIX via the intermediate thiocarbamate XX. ##STR12##

Scheme 4 shows another route to benzothiepine-1,1-dioxides Xc and Xd starting from the thiophenol XVIII. Compound XVIII can be reacted with mesylate IV to give the sulfide-aldehyde XXI. Oxidation of XXI with two equivalents of MCPBA yields the sulfone-aldehyde XIV which can be cyclized with potassium t-butoxide to a mixture of Xc and Xd. Cyclyzation of sulfide-aldehyde with potassium t-butoxide also gives a mixture of benzothiepine XXIIc and XXIId. ##STR13##

Examples of amine- and hydroxylamine-containing compounds of the present invention can be prepared as shown in Scheme 5 and Scheme 6. 2-Chloro-4-nitrobenzophenone is reduced with triethylsilane and trifluoromethane sulfonic acid to 2-chloro-4-nitrodiphenylmethane 32. Reaction of 32 with lithium sulfide followed by reacting the resulting sulfide with mesylate IV gives sulfide-aldehyde XXIII. Oxidation of XXIII with 2 equivalents of MCPBA yields sulfone-aldehyde XXIV which can be reduced by hydrogenation to the hydroxylamine XXV. Protecting the hydroxylamine XXV with di-t-butyldicarbonate gives the N,O-di-(t-butoxycarbonyl)hydroxylamino derivative XXVI. Cyclization of XXVI with potassium t-butoxide and removal of the t-butoxycarbonyl protecting group gives a mixture of hydroxylamino derivatives XXVIIc and XXVIId. The primary amine XXXIIIc and XXXIIId derivatives can also be prepared by further hydrogenation of XXIV or XXVIIc and XXVIId. ##STR14##

In Scheme 6, reduction of the sulfone-aldehyde XXV with hydrogen followed by reductive alkylation of the resulting amino derivative with hydrogen and an aldehyde catalyzed by palladium on carbon in the same reaction vessel yields the substituted amine derivative XXVIII. Cyclization of XXVIII with potassium t-butoxide yields a mixture of substituted amino derivatives of this invention XXIXC and XXIXd. ##STR15##

Scheme 7 describes one of the methods of introducing a substituent to the aryl ring at the 5-position of benzothiepine. Iodination of 5-phenyl derivative XXX with iodine catalyzed by mercuric triflate gives the iodo derivative XXXI, which upon palladium-catalyzed carbonylation in an alcohol yields the carboxylate XXXII. Hydrolysis of the carboxylate and derivatization of the resulting acid to acid derivatives are well known in the art. ##STR16##

Abbreviations used in the foregoing description have the following meanings:

THF--tetrahydrofuran

PTC--phase transfer catalyst

Aliquart 336--methyltricaprylylammonium chloride

MCPBA--m-chloroperbenzoic acid

Celite--a brand of diatomaceous earth filtering aid

DMF--dimethylformamide

DME--ethylene glycol dimethyl ether

BOC--t-butoxycarbonyl group

Me--methyl

Et--ethyl

Bu--butyl

EtOAc--ethyl acetate

Et₂ O--diethyl ether

CH₂ Cl₂ --methylene chloride

MgSO₄ --magnesium sulfate

NaOH--sodium hydroxide

CH₃ OH--methanol

HCl--hydrochloric acid

NaCl--sodium chloride

NaH--sodium hydride

LAH--lithium aluminum hydride

LiOH--lithium hydroxide

Na₂ SO₃ --sodium sulfite

NaHCO₃ --sodium bicarbonate

DMSO--dimethylsulfoxide

KOSiMe₃ --potassium trimethylsilanolate

PEG--polyethylene glycol

MS--mass spectrometry

HRMS--high resolution mass spectrometry

ES--electrospray

NMR--nuclear magnetic resonance spectroscopy

GC--gas chromatography

MPLC--medium pressure liquid chromatography

HPLC--high pressure liquid chromatography

RPHPLC--reverse phase high pressure liquid chromatography

RT--room temperature

h or hr--hour(s)

min--minute(s)

"Enantiomerically-enriched" (e.e.) means that one enantiomer or set of diastereomers preponderates over the complementary enantiomer or set of diastereomers. Enantiomeric enrichment of a mixture of enantiomers is calculated by dividing the concentration of the preponderating enantiomer by the concentration of the other enantiomer, multiplying the dividend by 100, and expressing the result as a percent. Enantiomeric enrichment can be from about 1% to about 100%, preferably from about 10% to about 100%, and more preferably from about 20% to 100%.

R¹ and R² can be selected from among substituted and unsubstituted C₁ to C₁₀ alkyl wherein the substituent(s) can be selected from among alkylcarbonyl, alkoxy, hydroxy, and nitrogen-containing heterocycles joined to the C₁ to C₁₀ alkyl through an ether linkage. Substituents at the 3-carbon can include ethyl, n-propyl, n-butyl, n-pentyl, isobutyl, isopropyl, --CH₂ C(═O)C₂ H₅, --CH₂ OC₂ H₅, and --CH₂ O-(4-picoline). Ethyl, n-propyl, n-butyl, and isobutyl are preferred. In certain particularly preferred compounds of the present invention, substituents R¹ and R² are identical, for example n-butyl/n-butyl, so that the compound is achiral at the 3-carbon. Eliminating optical isomerism at the 3-carbon simplifies the selection, synthesis, separation, and quality control of the compound used as an ileal bile acid transport inhibitor. In both compounds having a chiral 3-carbon and those having an achiral 3-carbon, substituents (R^(x)) on the benzo- ring can include hydrogen, aryl, alkyl, hydroxy, halo, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, haloalkyl, haloalkoxy, (N)-hydroxy-carbonylalkyl amine, haloalkylthio, haloalkylsulfinyl, haloalkylsufonyl, amino, N-alkylamino, N,N-dialkylamino, (N)-alkoxycarbamoyl, (N)-aryloxycarbamoyl, (N)-aralkyloxycarbamoyl, trialkylammonium (especially with a halide counterion), (N)-amido, (N)-alkylamido, -N-alkylamido, -N,N-dialkylamido, (N)-haloalkylamido, (N)-sulfonamido, (N)-alkylsulfonamido, (N)-haloalkylsulfonamido, carboxyalkyl-amino, trialkylammonium salt, (N)-carbamic acid, alkyl or benzyl ester, N-acylamine, hydroxylamine, haloacylamine, carbohydrate, thiophene a trialkyl ammonium salt having a carboxylic acid or hydroxy substituent on one or more of the alkyl substituents, an alkylene bridge having a quaternary ammonium salt substituted thereon, --[O(CH₂)_(w) ]_(x) --X where x is 2 to 12, w is 2 or 3 and X is a halo or a quaternary ammonium salt, and (N)-nitrogen containing heterocycle wherein the nitrogen of said heterocycle is optionally quaternized. Among the preferred species which may constitute R^(x) are methyl, ethyl, isopropyl, t-butyl, hydroxy, methoxy, ethoxy, isopropoxy, methylthio, iodo, bromo, fluoro, methylsulfinyl, methylsulfonyl, ethylthio, amino, hydroxylamine, N-methylamino, N,N-dimethylamino, N,N-diethylamino, (N)-benzyloxycarbamoyl, trimethylammonium, A⁻, --NHC(═O)CH₃, --NHC(═O)C₅ H₁₁, --NHC(═O)C₆ H₁₃, carboxyethylamino, (N)-morpholinyl, (N)-azetidinyl, (N)-N-methylazetidinium A⁻, (N)-pyrrolidinyl, pyrrolyl, (N)-N-methylpyridinium A⁻, (N)-N-methylmorpholinium A⁻, and N-N'-methylpiperazinyl, (N)-bromomethylamido, (N)-N-hexylamino, thiophene, --N⁺ (CH₃)₂ CO₂ H I⁻, --NCH₃ CH₂ CO₂ H, -(N)-N'-dimethylpiperazinium I⁻, (N)-t-butyloxycarbamoyl, (N)-methylsulfonamido, (N)N'-methylpyrrolidinium, and --(OCH₂ CH₂)₃ I, where A⁻ is a pharmaceutically acceptable anion. The benzo ring is can be mono-substituted at the 6, 7 or 8 position, or disubstituted at the 7- and -8 positions. Also included are the 6,7,8-trialkoxy compounds, for example the 6,7,8-trimethoxy compounds. A variety of other substituents can be advantageously present on the 6, 7, 8, and/or 9-positions of the benzo ring, including, for example, guanidinyl, cycloalkyl, carbohydrate (e.g., a 5 or 6 carbon monosaccharide), peptide, and quaternary ammonium salts linked to the ring via poly(oxyalkylene) linkages, e.g., --(OCH₂ CH₂)_(x) --N⁺ R¹³ R¹⁴ R¹⁵ A⁻, where x is 2 to 10. Exemplary compounds are those set forth below in Table 1.

                                      TABLE 1                                      __________________________________________________________________________     Alternative Compounds #3 (Family F101.xxx.yyy)                                  ##STR17##                                                                     Prefix                                                                         (FFF.xxx.yyy)                                                                         Cpd #                                                                              R.sup.1 ═R.sup.2                                                                    R.sup.5                                                                           (R.sup.x)q                                              __________________________________________________________________________     F101.001                                                                              01  ethyl    Ph--                                                                              7-methyl                                                       02  ethyl    Ph--                                                                              7-ethyl                                                        03  ethyl    Ph--                                                                              7-iso-propyl                                                   04  ethyl    Ph--                                                                              7-tert-butyl                                                   05  ethyl    Ph--                                                                              7-OH                                                           06  ethyl    Ph--                                                                              7-OCH.sub.3                                                    07  ethyl    Ph--                                                                              7-O(iso-propyl)                                                08  ethyl    Ph--                                                                              7-SCH.sub.3                                                    09  ethyl    Ph--                                                                              7-SOCH.sub.3                                                   10  ethyl    Ph--                                                                              7-SO.sub.2 CH.sub.3                                            11  ethyl    Ph--                                                                              7-SCH.sub.2 CH.sub.3                                           12  ethyl    Ph--                                                                              7-NH.sub.2                                                     13  ethyl    Ph--                                                                              7-NHOH                                                         14  ethyl    Ph--                                                                              7-NHCH.sub.3                                                   15  ethyl    Ph--                                                                              7-N(CH.sub.3).sub.2                                            16  ethyl    Ph--                                                                              7-N.sup.+ (CH.sub.3).sub.3, I.sup.-                            17  ethyl    Ph--                                                                              7-NHC(═O)CH.sub.3                                          18  ethyl    Ph--                                                                              7-N(CH.sub.2 CH.sub.3).sub.2                                   19  ethyl    Ph--                                                                              7-NMeCH.sub.2 CO.sub.2 H                                       20  ethyl    Ph--                                                                              7-N.sup.+ (Me).sub.2 CH.sub.2 CO.sub.2 H, I.sup.-              21  ethyl    Ph--                                                                              7-(N)-morpholine                                               22  ethyl    Ph--                                                                              7-(N)-azetidine                                                23  ethyl    Ph--                                                                              7-(N)-N-methylazetidinium, I.sup.-                             24  ethyl    Ph--                                                                              7-(N)-pyrrolidine                                              25  ethyl    Ph--                                                                              7-(N)-N-methyl-pyrrolidinium, I.sup.-                          26  ethyl    Ph--                                                                              7-(N)-N-methyl-morpholinium, I.sup.-                           27  ethyl    Ph--                                                                              7-(N)-N'-methylpiperazine                                      28  ethyl    Ph--                                                                              7-(N)-N'-dimethylpiperazinium, I.sup.-                         29  ethyl    Ph--                                                                              7-NH-CBZ                                                       30  ethyl    Ph--                                                                              7-NHC(O)C.sub.5 H.sub.11                                       31  ethyl    Ph--                                                                              7-NHC(O)CH.sub.2 Br                                            32  ethyl    Ph--                                                                              7-NH--C(NH)NH.sub.2                                            33  ethyl    Ph--                                                                              7-(2)-thiophene                                                34  ethyl    Ph--                                                                              8-methyl                                                       35  ethyl    Ph--                                                                              8-ethyl                                                        36  ethyl    Ph--                                                                              8-iso-propyl                                                   37  ethyl    Ph--                                                                              B-tert-butyl                                                   38  ethyl    Ph--                                                                              8-OH                                                           39  ethyl    Ph--                                                                              8-OCH.sub.3                                                    40  ethyl    Ph--                                                                              8-O(iso-propyl)                                                41  ethyl    Ph--                                                                              8-SCH.sub.3                                                    42  ethyl    Ph--                                                                              8-SOCH.sub.3                                                   43  ethyl    Ph--                                                                              8-SO.sub.2 CH.sub.3                                            44  ethyl    Ph--                                                                              8-SCH.sub.2 CH.sub.3                                           45  ethyl    Ph--                                                                              8-NH.sub.2                                                     46  ethyl    Ph--                                                                              8-NHOH                                                         47  ethyl    Ph--                                                                              8-NHCH.sub.3                                                   48  ethyl    Ph--                                                                              8-N(CH.sub.3).sub.2                                            49  ethyl    Ph--                                                                              8-N.sup.+ (CH.sub.3).sub.3, I.sup.-                            50  ethyl    Ph--                                                                              8-NHC(═O)CH.sub.3                                          51  ethyl    Ph--                                                                              8-N(CH.sub.2 CH.sub.3).sub.2                                   52  ethyl    Ph--                                                                              8-NMeCH.sub.2 CO.sub.2 H                                       53  ethyl    Ph--                                                                              8-N.sup.+ (Me).sub.2 CH.sub.2 CO.sub.2 H, I.sup.-              54  ethyl    Ph--                                                                              8-(N)-morpholine                                               55  ethyl    Ph--                                                                              8-(N)-azetidine                                                56  ethyl    Ph--                                                                              8-(N)-N-methylazetidinium, I.sup.-                             57  ethyl    Ph--                                                                              8-(N)-pyrrolidine                                              58  ethyl    Ph--                                                                              8-(N)-N-methyl-pyrrolidinium, I.sup.-                          59  ethyl    Ph--                                                                              8-(N)-N-methyl-morpholinium, I.sup.-                           60  ethyl    Ph--                                                                              8-(N)-N'-methylpiperazine                                      61  ethyl    Ph--                                                                              8-(N)-N'-dimethylpiperazinium, I.sup.-                         62  ethyl    Ph--                                                                              8-NH-CBZ                                                       63  ethyl    Ph--                                                                              8-NHC(O)C.sub.5 H.sub.11                                       64  ethyl    Ph--                                                                              8-NHC(O)CH.sub.2 Br                                            65  ethyl    Ph--                                                                              8-NH--C(NH)NH.sub.2                                            66  ethyl    Ph--                                                                              8-(2)-thiophene                                                67  ethyl    Ph--                                                                              9-methyl                                                       68  ethyl    Ph--                                                                              9-ethyl                                                        69  ethyl    Ph--                                                                              9-iso-propyl                                                   70  ethyl    Ph--                                                                              9-tert-butyl                                                   71  ethyl    Ph--                                                                              9-OH                                                           72  ethyl    Ph--                                                                              9-OCH.sub.3                                                    73  ethyl    Ph--                                                                              9-O(iso-propyl)                                                74  ethyl    Ph--                                                                              9-SCH.sub.3                                                    75  ethyl    Ph--                                                                              9-SOCH.sub.3                                                   76  ethyl    Ph--                                                                              9-SO.sub.2 CH.sub.3                                            77  ethyl    Ph--                                                                              9-SCH.sub.2 CH.sub.3                                           78  ethyl    Ph--                                                                              9-NH.sub.2                                                     79  ethyl    Ph--                                                                              9-NHOH                                                         80  ethyl    Ph--                                                                              9-NHCH.sub.3                                                   81  ethyl    Ph--                                                                              9-N(CH.sub.3).sub.2                                            82  ethyl    Ph--                                                                              9-N.sup.+ (CH.sub.3).sub.3, I.sup.-                            83  ethyl    Ph--                                                                              9-NHC(═O)CH.sub.3                                          84  ethyl    Ph--                                                                              9-N(CH.sub.2 CH.sub.3).sub.2                                   85  ethyl    Ph--                                                                              9-NMeCH.sub.2 CO.sub.2 H                                       86  ethyl    Ph--                                                                              9-N.sup.+ (Me).sub.2 CH.sub.2 CO.sub.2 H, I.sup.-              87  ethyl    Ph--                                                                              9-(N)-morpholine                                               88  ethyl    Ph--                                                                              9-(N)-azetidine                                                89  ethyl    Ph--                                                                              9-(N)-N-methylazetidinium, I.sup.-                             90  ethyl    Ph--                                                                              9-(N)-pyrrolidine                                              91  ethyl    Ph--                                                                              9-(N)-N-methyl-pyrrolidinium, I.sup.-                          92  ethyl    Ph--                                                                              9-(N)-N-methyl-morpholinium, I.sup.-                           93  ethyl    Ph--                                                                              9-(N)-N'-methylpiperazine                                      93  ethyl    Ph--                                                                              9-(N)-N'-dimethylpiperazinium, I.sup.-                         95  ethyl    Ph--                                                                              9-NH-CBZ                                                       96  ethyl    Ph--                                                                              9-NHC(O)C.sub.5 H.sub.11                                       97  ethyl    Ph--                                                                              9-NHC(O)CH.sub.2 Br                                            98  ethyl    Ph--                                                                              9-NH--C(NH)NH.sub.2                                            99  ethyl    Ph--                                                                              9-(2)-thiophene                                                100 ethyl    Ph--                                                                              7-OCH.sub.3, 8-OCH.sub.3                                       101 ethyl    Ph--                                                                              7-SCH.sub.3, 8-OCH.sub.3                                       102 ethyl    Ph--                                                                              7-SCH.sub.3, 8-SCH.sub.3                                       103 ethyl    Ph--                                                                              6-OCH.sub.3, 7-OCH.sub.3, 8-OCH.sub.3                   F101.002                                                                              01  n-propyl Ph--                                                                              7-methyl                                                       02  n-propyl Ph--                                                                              7-ethyl                                                        03  n-propyl Ph--                                                                              7-iso-propyl                                                   04  n-propyl Ph--                                                                              7-tert-butyl                                                   05  n-propyl Ph--                                                                              7-OH                                                           06  n-propyl Ph--                                                                              7-OCH.sub.3                                                    07  n-propyl Ph--                                                                              7-O(iso-propyl)                                                08  n-propyl Ph--                                                                              7-SCH.sub.3                                                    09  n-propyl Ph--                                                                              7-SOCH.sub.3                                                   10  n-propyl Ph--                                                                              7-SO.sub.2 CH.sub.3                                            11  n-propyl Ph--                                                                              7-SCH.sub.2 CH.sub.3                                           12  n-propyl Ph--                                                                              7-NH.sub.2                                                     13  n-propyl Ph--                                                                              7-NHOH                                                         14  n-propyl Ph--                                                                              7-NHCH.sub.3                                                   15  n-propyl Ph--                                                                              7-N(CH.sub.3).sub.2                                            16  n-propyl Ph--                                                                              7-N.sup.+ (CH.sub.3).sub.3, I.sup.-                            17  n-propyl Ph--                                                                              7-NHC(═O)CH.sub.3                                          18  n-propyl Ph--                                                                              7-N(CH.sub.2 CH.sub.3).sub.2                                   19  n-propyl Ph--                                                                              7-NMeCH.sub.2 CO.sub.2 H                                       20  n-propyl Ph--                                                                              7-N.sup.+ (Me).sub.2 CH.sub.2 CO.sub.2 H, I.sup.-              21  n-propyl Ph--                                                                              7-(N)-morpholine                                               22  n-propyl Ph--                                                                              7-(N)-azetidine                                                23  n-propyl Ph--                                                                              7-(N)-N-methylazetidinium, I.sup.-                             24  n-propyl Ph--                                                                              7-(N)-pyrrolidine                                              25  n-propyl Ph--                                                                              7-(N)-N-methyl-pyrrolidinium, I.sup.-                          26  n-propyl Ph--                                                                              7-(N)-N-methyl-morpholinium, I.sup.-                           27  n-propyl Ph--                                                                              7-(N)-N'-methylpiperazine                                      28  n-propyl Ph--                                                                              7-(N)-N'-dimethylpiperazinium, I.sup.-                         29  n-propyl Ph--                                                                              7-NH-CBZ                                                       30  n-propyl Fh-                                                                               7-NHC(O)C.sub.5 H.sub.11                                       31  n-propyl Ph--                                                                              7-NHC(O)CH.sub.2 Br                                            32  n-propyl Ph--                                                                              7-NH--C(NH)NH.sub.2                                            33  n-propyl Ph--                                                                              7-(2)-thiophene                                                34  n-propyl Ph--                                                                              8-methyl                                                       35  n-propyl Ph--                                                                              8-ethyl                                                        36  n-propyl Ph--                                                                              8-iso-propyl                                                   37  n-propyl Ph--                                                                              8-tert-butyl                                                   38  n-propyl Ph--                                                                              8-OH                                                           39  n-propyl Ph--                                                                              8-OCH.sub.3                                                    40  n-propyl Ph--                                                                              8-O(iso-propyl)                                                41  n-propyl Ph--                                                                              8-SCH.sub.3                                                    42  n-propyl Ph--                                                                              8-SOCH.sub.3                                                   43  n-propyl Ph--                                                                              8-SO.sub.2 CH.sub.3                                            44  n-propyl Ph--                                                                              8-SCH.sub.2 CH.sub.3                                           45  n-propyl Ph--                                                                              8-NH.sub.2                                                     46  n-propyl Ph--                                                                              8-NHOH                                                         47  n-propyl Ph--                                                                              8-NHCH.sub.3                                                   48  n-propyl Ph--                                                                              8-N(CH.sub.3).sub.2                                            49  n-propyl Ph--                                                                              8-N.sup.+ (CH.sub.3).sub.3, I.sup.-                            50  n-propyl Ph--                                                                              8-NHC(═O)CH.sub.3                                          51  n-propyl Ph--                                                                              8-N(CH.sub.2 CH.sub.3).sub.2                                   52  n-propyl Ph--                                                                              8-NMeCH.sub.2 CO.sub.2 H                                       53  n-propyl Ph--                                                                              8-N.sup.+ (Me).sub.2 CH.sub.2 CO.sub.2 H, I.sup.-              54  n-propyl Ph--                                                                              8-(N)-morpholine                                               55  n-propyl Ph--                                                                              8-(N)-azetidine                                                56  n-propyl Ph--                                                                              8-(N)-N-methylazetidinium, I.sup.-                             57  n-propyl Ph--                                                                              8-(N)-pyrrolidine                                              58  n-propyl Ph--                                                                              8-(N)-N-methyl-pyrrolidinium, I.sup.-                          59  n-propyl Ph--                                                                              8-(N)-N-methyl-morpholinium, I.sup.-                           60  n-propyl Ph--                                                                              8-(N)-N'-methylpiperazine                                      61  n-propyl Ph--                                                                              8-(N)-N'-dimethylpiperazinium, I.sup.-                         62  n-propyl Ph--                                                                              8-NH-CBZ                                                       63  n-propyl Ph--                                                                              8-NHC(O)C.sub.5 H.sub.11                                       64  n-propyl Ph--                                                                              8-NHC(O)CH.sub.2 Br                                            65  n-propyl Ph--                                                                              8-NH--C(NH)NH.sub.2                                            66  n-propyl Ph--                                                                              8-(2)-thiophene                                                67  n-propyl Ph--                                                                              9-methyl                                                       68  n-propyl Ph--                                                                              9-ethyl                                                        69  n-propyl Ph--                                                                              9-iso-propyl                                                   70  n-propyl Ph--                                                                              9-tert-butyl                                                   71  n-propyl Ph--                                                                              9-OH                                                           72  n-propyl Ph--                                                                              9-OCH.sub.3                                                    73  n-propyl Ph--                                                                              9-O(iso-propyl)                                                74  n-propyl Ph--                                                                              9-SCH.sub.3                                                    75  n-propyl Ph--                                                                              9-SOCH.sub.3                                                   76  n-propyl Ph--                                                                              9-SO.sub.2 CH.sub.3                                            77  n-propyl Ph--                                                                              9-SCH.sub.2 CH.sub.3                                           78  n-propyl Ph--                                                                              9-NH.sub.2                                                     79  n-propyl Ph--                                                                              9-NHOH                                                         80  n-propyl Ph--                                                                              9-NHCH.sub.3                                                   81  n-propyl Ph--                                                                              9-N(CH.sub.3).sub.2                                            82  n-propyl Ph--                                                                              9-N.sup.+ (CH.sub.3).sub.3, I.sup.-                            83  n-propyl Ph--                                                                              9-NHC(═O)CH.sub.3                                          84  n-propyl Ph--                                                                              9-N(CH.sub.2 CH.sub.3).sub.2                                   85  n-propyl Ph--                                                                              9-NMeCH.sub.2 CO.sub.2 H                                       86  n-propyl Ph--                                                                              9-N.sup.+ (Me).sub.2 CH.sub.2 CO.sub.2 H, I.sup.-              87  n-propyl Ph--                                                                              9-(N)-morpholine                                               88  n-propyl Ph--                                                                              9-(N)-azetidine                                                89  n-propyl Ph--                                                                              9-(N)-N-methylazetidinium, I.sup.-                             90  n-propyl Ph--                                                                              9-(N)-pyrrolidine                                              91  n-propyl Ph--                                                                              9-(N)-N-methyl-pyrrolidinium, I.sup.-                          92  n-propyl Ph--                                                                              9-(N)-N-methyl-morpholinium, I.sup.-                           93  n-propyl Ph--                                                                              9-(N)-N'-methylpiperazine                                      93  n-propyl Ph--                                                                              9-(N)-N'-dimethylpiperazinium, I.sup.-                         95  n-propyl Ph--                                                                              9-NH-CBZ                                                       96  n-propyl Ph--                                                                              9-NHC(O)C.sub.5 H.sub.11                                       97  n-propyl Ph--                                                                              9-NHC(O)CH.sub.2 Br                                            98  n-propyl Ph--                                                                              9-NH--C(NH)NH.sub.2                                            99  n-propyl Ph--                                                                              9-(2)-thiophene                                                100 n-propyl Ph--                                                                              7-OCH.sub.3, 8-OCH.sub.3                                       101 n-propyl Ph--                                                                              7-SCH.sub.3, 8-OCH.sub.3                                       102 n-propyl Ph--                                                                              7-SCH.sub.3, 8-SCH.sub.3                                       103 n-propyl Ph--                                                                              6-OCH.sub.3, 7-OCH.sub.3, 8-OCH.sub.3                   F101.003                                                                              01  n-butyl  Ph--                                                                              7-methyl                                                       02  n-butyl  Ph--                                                                              7-ethyl                                                        03  n-butyl  Ph--                                                                              7-iso-propyl                                                   04  n-butyl  Ph--                                                                              7-tert-butyl                                                   05  n-butyl  Ph--                                                                              7-OH                                                           06  n-butyl  Ph--                                                                              7-OCH.sub.3                                                    07  n-butyl  Ph--                                                                              7-O(iso-propyl)                                                08  n-butyl  Ph--                                                                              7-SCH.sub.3                                                    09  n-butyl  Ph--                                                                              7-SOCH.sub.3                                                   10  n-butyl  Ph--                                                                              7-SO.sub.2 CH.sub.3                                            11  n-butyl  Ph--                                                                              7-SCH.sub.2 CH.sub.3                                           12  n-butyl  Ph--                                                                              7-NH.sub.2                                                     13  n-butyl  Ph--                                                                              7-NHOH                                                         14  n-butyl  Ph--                                                                              7-NHCH.sub.3                                                   15  n-butyl  Ph--                                                                              7-N(CH.sub.3).sub.2                                            16  n-butyl  Ph--                                                                              7-N.sup.+ (CH.sub.3).sub.3, I.sup.-                            17  n-butyl  Ph--                                                                              7-NHC(═O)CH.sub.3                                          18  n-butyl  Ph--                                                                              7-N(CH.sub.2 CH.sub.3).sub.2                                   19  n-butyl  Ph--                                                                              7-NMeCH.sub.2 CO.sub.2 H                                       20  n-butyl  Ph--                                                                              7-N.sup.+ (Me).sub.2 CH.sub.2 CO.sub.2 H, I.sup.-              21  n-butyl  Ph--                                                                              7-(N)-morpholine                                               22  n-butyl  Ph--                                                                              7-(N)-azetidine                                                23  n-butyl  Ph--                                                                              7-(N)-N-methylazetidinium, I.sup.-                             24  n-butyl  Ph--                                                                              7-(N)-pyrrolidine                                              25  n-butyl  Ph--                                                                              7-(N)-N-methyl-pyrrolidinium, I.sup.-                          26  n-butyl  Ph--                                                                              7-(N)-N-methyl-morpholinium, I.sup.-                           27  n-butyl  Ph--                                                                              7-(N)-N'-methylpiperazine                                      28  n-butyl  Ph--                                                                              7-(N)-N'-dimethylpiperazinium, I.sup.-                         29  n-butyl  Ph--                                                                              7-NH-CBZ                                                       30  n-butyl  Ph--                                                                              7-NHC(O)C.sub.5 H.sub.11                                       31  n-butyl  Ph--                                                                              7-NHC(O)CH.sub.2 Br                                            32  n-butyl  Ph--                                                                              7-NH--C(NH)NH.sub.2                                            33  n-butyl  Ph--                                                                              7-(2)-thiophene                                                34  n-butyl  Ph--                                                                              8-methyl                                                       35  n-butyl  Ph--                                                                              8-ethyl                                                        36  n-butyl  Ph--                                                                              8-iso-propyl                                                   37  n-butyl  Ph--                                                                              8-tert-butyl                                                   38  n-butyl  Ph--                                                                              8-OH                                                           39  n-butyl  Ph--                                                                              8-OCH.sub.3                                                    40  n-butyl  Ph--                                                                              8-O(iso-propyl)                                                41  n-butyl  Ph--                                                                              8-SCH.sub.3                                                    42  n-butyl  Ph--                                                                              8-SOCH.sub.3                                                   43  n-butyl  Ph--                                                                              8-SO.sub.2 CH.sub.3                                            44  n-butyl  Ph--                                                                              8-SCH.sub.2 CH.sub.3                                           45  n-butyl  Ph--                                                                              8-NH.sub.2                                                     46  n-butyl  Ph--                                                                              8-NHOH                                                         47  n-butyl  Ph--                                                                              8-NHCH.sub.3                                                   48  n-butyl  Ph--                                                                              8-N(CH.sub.3).sub.2                                            49  n-butyl  Ph--                                                                              8-N.sup.+ (CH.sub.3).sub.3, I.sup.-                            50  n-butyl  Ph--                                                                              8-NHC(═O)CH.sub.3                                          51  n-butyl  Ph--                                                                              8-N(CH.sub.2 CH.sub.3).sub.2                                   52  n-butyl  Ph--                                                                              8-NMeCH.sub.2 CO.sub.2 H                                       53  n-butyl  Ph--                                                                              8-N.sup.+ (Me).sub.2 CH.sub.2 CO.sub.2 H1 I.sup.-              54  n-butyl  Ph--                                                                              8-(N)-morpholine                                               55  n-butyl  Ph--                                                                              8-(N)-azetidine                                                56  n-butyl  Ph--                                                                              8-(N)-N-methylazetidinium, I.sup.-                             57  n-butyl  Ph--                                                                              8-(N)-pyrrolidine                                              58  n-butyl  Ph--                                                                              8-(N)-N-methyl-pyrrolidinium, I.sup.-                          59  n-butyl  Ph--                                                                              8-(N)-N-methyl-morpholinium, I.sup.-                           60  n-butyl  Ph--                                                                              8-(N)-N'-methylpiperazine                                      61  n-butyl  Ph--                                                                              8-(N)-N'-dimethylpiperazinium, I.sup.-                         62  n-butyl  Ph--                                                                              8-NH-CBZ                                                       63  n-butyl  Ph--                                                                              8-NHC(O)C.sub.5 H.sub.11                                       64  n-butyl  Ph--                                                                              8-NHC(O)CH.sub.2 Br                                            65  n-butyl  Ph--                                                                              8-NH--C(NH)NH.sub.2                                            66  n-butyl  Ph--                                                                              8-(2)-thiophene                                                67  n-butyl  Ph--                                                                              9-methyl                                                       68  n-butyl  Ph--                                                                              9-ethyl                                                        69  n-butyl  Ph--                                                                              9-iso-propyl                                                   70  n-butyl  Ph--                                                                              9-tert-butyl                                                   71  n-butyl  Ph--                                                                              9-OH                                                           72  n-butyl  Ph--                                                                              9-OCH.sub.3                                                    73  n-butyl  Ph--                                                                              9-O(iso-propyl)                                                74  n-butyl  Ph--                                                                              9-SCH.sub.3                                                    75  n-butyl  Ph--                                                                              9-SOCH.sub.3                                                   76  n-butyl  Ph--                                                                              9-SO.sub.2 CH.sub.3                                            77  n-butyl  Ph--                                                                              9-SCH.sub.2 CH.sub.3                                           78  n-butyl  Ph--                                                                              9-NH.sub.2                                                     79  n-butyl  Ph--                                                                              9-NHOH                                                         80  n-butyl  Ph--                                                                              9-NHCH.sub.3                                                   81  n-butyl  Ph--                                                                              9-N(CH.sub.3).sub.2                                            82  n-butyl  Ph--                                                                              9-N.sup.+ (CH.sub.3).sub.3, I.sup.-                            83  n-butyl  Ph--                                                                              9-NHC(═O)CH.sub.3                                          84  n-butyl  Ph--                                                                              9-N(CH.sub.2 CH.sub.3).sub.2                                   85  n-butyl  Ph--                                                                              9-NMeCH.sub.2 CO.sub.2 H                                       86  n-butyl  Ph--                                                                              9-N.sup.+ (Me).sub.2 CH.sub.2 CO.sub.2 H, I.sup.-              87  n-butyl  Ph--                                                                              9-(N)-morpholine                                               88  n-butyl  Ph--                                                                              9-(N)-azetidine                                                89  n-butyl  Ph--                                                                              9-(N)-N-methylazetidinium, I.sup.-                             90  n-butyl  Ph--                                                                              9-(N)-pyrrolidine                                              91  n-butyl  Ph--                                                                              9-(N)-N-methyl-pyrrolidinium, I.sup.-                          92  n-butyl  Ph--                                                                              9-(N)-N-methyl-morpholinium, I.sup.-                           93  n-butyl  Ph--                                                                              9-(N)-N'-methylpiperazine                                      93  n-butyl  Ph--                                                                              9-(N)-N'-dimethylpiperazinium, I.sup.-                         95  n-butyl  Ph--                                                                              9-NH-CBZ                                                       96  n-butyl  Ph--                                                                              9-NHC(O)C.sub.5 H.sub.11                                       97  n-butyl  Ph--                                                                              9-NHC(O)CH.sub.2 Br                                            98  n-butyl  Ph--                                                                              9-NH--C(NH)NH.sub.2                                            99  n-butyl  Ph--                                                                              9-(2)-thiophene                                                100 n-butyl  Ph--                                                                              7-OCH.sub.3, 8-OCH.sub.3                                       101 n-butyl  Ph--                                                                              7-SCH.sub.3, 8-OCH.sub.3                                       102 n-butyl  Ph--                                                                              7-SCH.sub.3, 8-SCH.sub.3                                       103 n-butyl  Ph--                                                                              6-OCH.sub.3, 7-OCH.sub.3, 8-OCH.sub.3                   F101.004                                                                              01  n-pentyl Ph--                                                                              7-methyl                                                       02  n-pentyl Ph--                                                                              7-ethyl                                                        03  n-pentyl Ph--                                                                              7-iso-propyl                                                   04  n-pentyl Ph--                                                                              7-tert-butyl                                                   05  n-pentyl Ph--                                                                              7-OH                                                           06  n-pentyl Ph--                                                                              7-OCH.sub.3                                                    07  n-pentyl Ph--                                                                              7-O(iso-propyl)                                                08  n-pentyl Ph--                                                                              7-SCH.sub.3                                                    09  n-pentyl Ph--                                                                              7-SOCH.sub.3                                                   10  n-pentyl Ph--                                                                              7-SO.sub.2 CH.sub.3                                            11  n-pentyl Ph--                                                                              7-SCH.sub.2 CH.sub.3                                           12  n-pentyl Ph--                                                                              7-NH.sub.2                                                     13  n-pentyl Ph--                                                                              7-NHQH                                                         14  n-pentyl Ph--                                                                              7-NHCH.sub.3                                                   15  n-pentyl Ph--                                                                              7-N(CH.sub.3).sub.2                                            16  n-pentyl Ph--                                                                              7-N.sup.+ (CH.sub.3).sub.3, I.sup.-                            17  n-pentyl Ph--                                                                              7-NHC(═O)CH.sub.3                                          18  n-pentyl Ph--                                                                              7-N(CH.sub.2 CH.sub.3).sub.2                                   19  n-pentyl Ph--                                                                              7-NMeCH.sub.2 CO.sub.2 H                                       20  n-pentyl Ph--                                                                              7-N.sup.+ (Me).sub.2 CH.sub.2 CO.sub.2 H, I.sup.-              21  n-pentyl Ph--                                                                              7-(N)-morpholine                                               22  n-pentyl Ph--                                                                              7-(N)-azetidine                                                23  n-pentyl Ph--                                                                              7-(N)-N-methylazetidinium, I.sup.-                             24  n-pentyl Ph--                                                                              7-(N)-pyrrolidine                                              25  n-pentyl Ph--                                                                              7-(N)-N-methyl-pyrrolidinium, I.sup.-                          26  n-pentyl Ph--                                                                              7-(N)-N-methyl-morpholinium, I.sup.-                           27  n-pentyl Ph--                                                                              7-(N)-N'-methylpiperazine                                      28  n-pentyl Ph--                                                                              7-(N)-N'-dimethylpiperazinium, I.sup.-                         29  n-pentyl Ph--                                                                              7-NH-CBZ                                                       30  n-pentyl Ph--                                                                              7-NHC(O)C.sub.5 H.sub.11                                       31  n-pentyl Ph--                                                                              7-NHC(O)CH.sub.2 Br                                            32  n-pentyl Ph--                                                                              7-NH--C(NH)NH.sub.2                                            33  n-pentyl Ph--                                                                              7-(2)-thiophene                                                34  n-pentyl Ph--                                                                              8-methyl                                                       35  n-pentyl Ph--                                                                              8-ethyl                                                        36  n-pentyl Ph--                                                                              8-iso-propyl                                                   37  n-pentyl Ph--                                                                              8-tert-butyl                                                   38  n-pentyl Ph--                                                                              8-OH                                                           39  n-pentyl Ph--                                                                              8-OCH.sub.3                                                    40  n-pentyl Ph--                                                                              8-O(iso-propyl)                                                41  n-pentyl Ph--                                                                              8-SCH.sub.3                                                    42  n-pentyl Ph--                                                                              8-SOCH.sub.3                                                   43  n-pentyl Ph--                                                                              8-SO.sub.2 CH.sub.3                                            44  n-pentyl Ph--                                                                              8-SCH.sub.2 CH.sub.3                                           45  n-pentyl Ph--                                                                              8-NH.sub.2                                                     46  n-pentyl Ph--                                                                              8-NHOH                                                         47  n-pentyl Ph--                                                                              8-NHCH.sub.3                                                   48  n-pentyl Ph--                                                                              8-N(CH.sub.3).sub.2                                            49  n-pentyl Ph--                                                                              8-N.sup.+ (CH.sub.3).sub.3, I.sup.-                            50  n-pentyl Ph--                                                                              8-NHC(═O)CH.sub.3                                          51  n-pentyl Ph--                                                                              8-N(CH.sub.2 CH.sub.3).sub.2                                   52  n-pentyl Ph--                                                                              8-NMeCH.sub.2 CO.sub.2 H                                       53  n-pentyl Ph--                                                                              8-N.sup.+ (Me).sub.2 CH.sub.2 CO.sub.2 H, I.sup.-              54  n-pentyl Ph--                                                                              8-(N)-morpholine                                               55  n-pentyr Ph--                                                                              8-(N)-azetidine                                                56  n-pentyl Ph--                                                                              8-(N)-N-methylazetidinium, I.sup.-                             57  n-pentyl Ph--                                                                              8-(N)-pyrrolidine                                              58  n-pentyl Ph--                                                                              8-(N)-N-methyl-pyrrolidinium, I.sup.-                          59  n-pentyl Ph--                                                                              8-(N)-N-methyl-morpholinium, I.sup.-                           60  n-pentyl Ph--                                                                              8-(N)-N'-methylpiperazine                                      61  n-pentyl Ph--                                                                              8-(N)-N'-dimethylpiperazinium, I.sup.-                         62  n-pentyl Ph--                                                                              8-NH-CBZ                                                       63  n-pentyl Ph--                                                                              8-NHC(O)C.sub.5 H.sub.11                                       64  n-pentyl Ph--                                                                              8-NHC(O)CH.sub.2 Br                                            65  n-pentyl Ph--                                                                              8-NH--C(NH)NH.sub.2                                            66  n-pentyl Ph--                                                                              8-(2)-thiophene                                                67  n-pentyl Ph--                                                                              9-methyl                                                       68  n-pentyl Ph--                                                                              9-ethyl                                                        69  n-pentyl Ph--                                                                              9-iso-propyl                                                   70  n-pentyl Ph--                                                                              9-tert-butyl                                                   71  n-pentyl Ph--                                                                              9-OH                                                           72  n-pentyl Ph--                                                                              9-OCH.sub.3                                                    73  n-pentyl Ph--                                                                              9-O(iso-propyl)                                                74  n-pentyl Ph--                                                                              9-SCH.sub.3                                                    75  n-pentyl Ph--                                                                              9-SOCH.sub.3                                                   76  n-pentyl Ph--                                                                              9-SO.sub.2 CH.sub.3                                            77  n-pentyl Ph--                                                                              9-SCH.sub.2 CH.sub.3                                           78  n-pentyl Ph--                                                                              9-NH.sub.2                                                     79  n-pentyl Ph--                                                                              9-NHOH                                                         80  n-pentyl Ph--                                                                              9-NHCH.sub.3                                                   81  n-pentyl Ph--                                                                              9-N(CH.sub.3).sub.2                                            82  n-pentyl Ph--                                                                              9-N.sup.+ (CH.sub.3).sub.3, I.sup.-                            83  n-pentyl Ph--                                                                              9-NHC(═O)CH.sub.3                                          84  n-pentyl Ph--                                                                              9-N(CH.sub.2 CH.sub.3).sub.2                                   85  n-pentyl Ph--                                                                              9-NMeCH.sub.2 CO.sub.2 H                                       86  n-pentyl Ph--                                                                              9-N.sup.+ (Me).sub.2 CH.sub.2 CO.sub.2 H, I.sup.-              87  n-pentyl Ph--                                                                              9-(N)-morpholine                                               88  n-pentyl Ph--                                                                              9-(N)-azetidine                                                89  n-pentyl Ph--                                                                              9-(N)-N-methylazetidinium, I.sup.-                             90  n-pentyl Ph--                                                                              9-(N)-pyrrolidine                                              91  n-pentyl Ph--                                                                              9-(N)-N-methyl-pyrrolidinium, I.sup.-                          92  n-pentyl Ph--                                                                              9-(N)-N-methyl-morpholinium, I.sup.-                           93  n-pentyl Ph--                                                                              9-(N)-N'-methylpiperazine                                      93  n-pentyl Ph--                                                                              9-(N)-N'-dimethylpiperazinium, I.sup.-                         95  n-pentyl Ph--                                                                              9-NH-CBZ                                                       96  n-pentyl Ph--                                                                              9-NHC(O)C.sub.5 H.sub.11                                       97  n-pentyl Ph--                                                                              9-NHC(O)CH.sub.2 Br                                            98  n-pentyl Ph--                                                                              9-NH--C(NH)NH.sub.2                                            99  n-pentyl Ph--                                                                              9-(2)-thiophene                                                100 n-pentyl Ph--                                                                              7-OCH.sub.3, 8-OCH.sub.3                                       101 n-pentyl Ph--                                                                              7-SCH.sub.3, 8-OCH.sub.3                                       102 n-pentyl Ph--                                                                              7-SCH.sub.3, 8-SCH.sub.3                                       103 n-pentyl Ph--                                                                              6-OCH.sub.3, 7-OCH.sub.3, 8-OCH.sub.3                   F101.005                                                                              01  n-hexyl  Ph--                                                                              7-methyl                                                       02  n-hexyl  Ph--                                                                              7-ethyl                                                        03  n-hexyl  Ph--                                                                              7-iso-propyl                                                   04  n-hexyl  Ph--                                                                              7-tert-butyl                                                   05  n-hexyl  Ph--                                                                              7-OH                                                           06  n-hexyl  Ph--                                                                              7-OCH.sub.3                                                    07  n-hexyl  Ph--                                                                              7-O(iso-propyl)                                                08  n-hexyl  Ph--                                                                              7-SCH.sub.3                                                    09  n-hexyl  Ph--                                                                              7-SOCH.sub.3                                                   10  n-hexyl  Ph--                                                                              7-SO.sub.2 CH.sub.3                                            11  n-hexyl  Ph--                                                                              7-SCH.sub.2 CH.sub.3                                           12  n-hexyl  Ph--                                                                              7-NH.sub.2                                                     13  n-hexyl  Ph--                                                                              7-NHOH                                                         14  n-hexyl  Ph--                                                                              7-NHCH.sub.3                                                   15  n-hexyl  Ph--                                                                              7-N(CH.sub.3).sub.2                                            16  n-hexyl  Ph--                                                                              7-N.sup.+ (CH.sub.3).sub.3, I.sup.-                            17  n-hexyl  Ph--                                                                              7-NHC(═O)CH.sub.3                                          18  n-hexyl  Ph--                                                                              7-N(CH.sub.2 CH.sub.3).sub.2                                   19  n-hexyl  Ph--                                                                              7-NMeCH.sub.2 CO.sub.2 H                                       20  n-hexyl  Ph--                                                                              7-N.sup.+ (Me).sub.2 CH.sub.2 CO.sub.2 H, I.sup.-              21  n-hexyl  Ph--                                                                              7-(N)-morpholine                                               22  n-hexyl  Ph--                                                                              7-(N)-azetidine                                                23  n-hexyl  Ph--                                                                              7-(N)-N-methylazetidinium, I.sup.-                             24  n-hexyl  Ph--                                                                              7-(N)-pyrrolidine                                              25  n-hexyl  Ph--                                                                              7-(N)-N-methyl-pyrrolidinium, I.sup.-                          26  n-hexyl  Ph--                                                                              7-(N)-N-methyl-morpholinium, I.sup.-                           27  n-hexyl  Ph--                                                                              7-(N)-N'-methylpiperazine                                      28  n-hexyl  Ph--                                                                              7-(N)-N'-dimethylpiperazinium, I.sup.-                         29  n-hexyl  Ph--                                                                              7-NH-CBZ                                                       30  n-hexyl  Ph--                                                                              7-NHC(O)C.sub.5 H.sub.11                                       31  n-hexyl  Ph--                                                                              7-NHC(O)CH.sub.2 Br                                            32  n-hexyl  Ph--                                                                              7-NH--C(NH)NH.sub.2                                            33  n-hexyl  Ph--                                                                              7-(2)-thiophene                                                34  n-hexyl  Ph--                                                                              8-methyl                                                       35  n-hexyl  Ph--                                                                              8-ethyl                                                        36  n-hexyl  Ph--                                                                              8-iso-propyl                                                   37  n-hexyl  Ph--                                                                              8-tert-butyl                                                   38  n-hexyl  Ph--                                                                              8-OH                                                           39  n-hexyl  Ph--                                                                              8-OCH.sub.3                                                    40  n-hexyl  Ph--                                                                              8-O(iso-propyl)                                                41  n-hexyl  Ph--                                                                              8-SCH.sub.3                                                    42  n-hexyl  Ph--                                                                              8-SOCH.sub.3                                                   43  n-hexyl  Ph--                                                                              8-SO.sub.2 CH.sub.3                                            44  n-hexyl  Ph--                                                                              8-SCH.sub.2 CH.sub.3                                           45  n-hexyl  Ph--                                                                              8-NH.sub.2                                                     46  n-hexyl  Ph--                                                                              8-NHOH                                                         47  n-hexyl  Ph--                                                                              8-NHCH.sub.3                                                   48  n-hexyl  Ph--                                                                              8-N(CH.sub.3).sub.2                                            49  n-hexyl  Ph--                                                                              8-N.sup.+ (CH.sub.3).sub.3, I.sup.-                            50  n-hexyl  Ph--                                                                              8-NHC(═O)CH.sub.3                                          51  n-hexyl  Ph--                                                                              8-N(CH.sub.2 CH.sub.3).sub.2                                   52  n-hexyl  Ph--                                                                              8-NMeCH.sub.2 CO.sub.2 H                                       53  n-hexyl  Ph--                                                                              8-N.sup.+ (Me).sub.2 CH.sub.2 CO.sub.2 H, I.sup.-              54  n-hexyl  Ph--                                                                              8-(N)-morpholine                                               55  n-hexyl  Ph--                                                                              8-(N)-azetidine                                                56  n-hexyl  Ph--                                                                              8-(N)-N-methylazetidinium, I.sup.-                             57  n-hexyl  Ph--                                                                              8-(N)-pyrrolidine                                              58  n-hexyl  Ph--                                                                              8-(N)-N-methyl-pyrrolidinium, I.sup.-                          59  n-hexyl  Ph--                                                                              8-(N)-N-methyl-morpholinium, I.sup.-                           60  n-hexyl  Ph--                                                                              8-(N)-N'-methylpiperazine                                      61  n-hexyl  Ph--                                                                              8-(N)-N'-dimethylpiperazinium, I.sup.-                         62  n-hexyl  Ph--                                                                              8-NH-CBZ                                                       63  n-hexyl  Ph--                                                                              8-NHC(O)C.sub.5 H.sub.11                                       64  n-hexyl  Ph--                                                                              8-NHC(O)CH.sub.2 Br                                            65  n-hexyl  Ph--                                                                              8-NH--C(NH)NH.sub.2                                            66  n-hexyl  Ph--                                                                              8-(2)-thiophene                                                67  n-hexyl  Ph--                                                                              9-methyl                                                       68  n-hexyl  Ph--                                                                              9-ethyl                                                        69  n-hexyl  Ph--                                                                              9-iso-propyl                                                   70  n-hexyl  Ph--                                                                              9-tert-butyl                                                   71  n-hexyl  Ph--                                                                              9-OH                                                           72  n-hexyl  Ph--                                                                              9-OCH.sub.3                                                    73  n-hexyl  Ph--                                                                              9-O(iso-propyl)                                                74  n-hexyl  Ph--                                                                              9-SCH.sub.3                                                    75  n-hexyl  Ph--                                                                              9-SOCH.sub.3                                                   76  n-hexyl  Ph--                                                                              9-SO.sub.2 CH.sub.3                                            77  n-hexyl  Ph--                                                                              9-SCH.sub.2 CH.sub.3                                           78  n-hexyl  Ph--                                                                              9-NH.sub.2                                                     79  n-hexyl  Ph--                                                                              9-NHOH                                                         80  n-hexyl  Ph--                                                                              9-NHCH.sub.3                                                   81  n-hexyl  Ph--                                                                              9-N(CH.sub.3).sub.2                                            82  n-hexyl  Ph--                                                                              9-N.sup.+ (CH.sub.3).sub.3, I.sup.-                            83  n-hexyl  Ph--                                                                              9-NHC(═O)CH.sub.3                                          84  n-hexyl  Ph--                                                                              9-N(CH.sub.2 CH.sub.3).sub.2                                   85  n-hexyl  Ph--                                                                              9-NMeCH.sub.2 CO.sub.2 H                                       86  n-hexyl  Ph--                                                                              9-N.sup.+ (Me).sub.2 CH.sub.2 CO.sub.2 H, I.sup.-              87  n-hexyl  Ph--                                                                              9-(N)-morpholine                                               88  n-hexyl  Ph--                                                                              9-(N)-azetidine                                                89  n-hexyl  Ph--                                                                              9-(N)-N-methylazetidinium, I.sup.-                             90  n-hexyl  Ph--                                                                              9-(N)-pyrrolidine                                              91  n-hexyl  Ph--                                                                              9-(N)-N-methyl-pyrrolidinium, I.sup.-                          92  n-hexyl  Ph--                                                                              9-(N)-N-methyl-morpholinium, I.sup.-                           93  n-hexyl  Ph--                                                                              9-(N)-N'-methylpiperazine                                      93  n-hexyl  Ph--                                                                              9-(N)-N'-dimethylpiperazinium, I.sup.-                         95  n-hexyl  Ph--                                                                              9-NH-CBZ                                                       96  n-hexyl  Ph--                                                                              9-NHC(O)C.sub.5 H.sub.11                                       97  n-hexyl  Ph--                                                                              9-NHC(O)CH.sub.2 Br                                            98  n-hexyl  Ph--                                                                              9-NH--C(NH)NH.sub.2                                            99  n-hexyl  Ph--                                                                              9-(2)-thiophene                                                100 n-hexyl  Ph--                                                                              7-OCH.sub.3, 8-OCH.sub.3                                       101 n-hexyl  Ph--                                                                              7-SCH.sub.3, 8-OCH.sub.3                                       102 n-hexyl  Ph--                                                                              7-SCH.sub.3, 8-SCH.sub.3                                       103 n-hexyl  Ph--                                                                              6-OCH.sub.3, 7-OCH.sub.3, 8-OCH.sub.3                   F101.006                                                                              01  iso-propyl                                                                              Ph--                                                                              7-methyl                                                       02  iso-propyl                                                                              Ph--                                                                              7-ethyl                                                        03  iso-propyl                                                                              Ph--                                                                              7-iso-propyl                                                   04  iso-propyl                                                                              Ph--                                                                              7-tert-butyl                                                   05  iso-propyl                                                                              Ph--                                                                              7-OH                                                           06  iso-propyl                                                                              Ph--                                                                              7-OCH.sub.3                                                    07  iso-propyl                                                                              Ph--                                                                              7-O(iso-propyl)                                                08  iso-propyl                                                                              Ph--                                                                              7-SCH.sub.3                                                    09  iso-propyl                                                                              Ph--                                                                              7-SOCH.sub.3                                                   10  iso-propyl                                                                              Ph--                                                                              7-SO.sub.2 CH.sub.3                                            11  iso-propyl                                                                              Ph--                                                                              7-SCH.sub.2 CH.sub.3                                           12  iso-propyl                                                                              Ph--                                                                              7-NH.sub.2                                                     13  iso-propyl                                                                              Ph--                                                                              7-NHOH                                                         14  iso-propyl                                                                              Ph--                                                                              7-NHCH.sub.3                                                   15  iso-propyl                                                                              Ph--                                                                              7-N(CH.sub.3).sub.2                                            16  iso-propyl                                                                              Ph--                                                                              7-N.sup.+ (CH.sub.3).sub.3, I.sup.-                            17  iso-propyl                                                                              Ph--                                                                              7-NHC(═O)CH.sub.3                                          18  iso-propyl                                                                              Ph--                                                                              7-N(CH.sub.2 CH.sub.3).sub.2                                   19  iso-propyl                                                                              Ph--                                                                              7-NMeCH.sub.2 CO.sub.2 H                                       20  iso-propyl                                                                              Ph--                                                                              7-N.sup.+ (Me).sub.2 CH.sub.2 CO.sub.2 H, I.sup.-              21  iso-propyl                                                                              Ph--                                                                              7-(N)-morpholine                                               22  iso-propyl                                                                              Ph--                                                                              7-(N)-azetidine                                                23  iso-propyl                                                                              Ph--                                                                              7-(N)-N-methylazetidinium, I.sup.-                             24  iso-propyl                                                                              Ph--                                                                              7-(N)-pyrrolidine                                              25  iso-propyl                                                                              Ph--                                                                              7-(N)-N-methyl-pyrrolidinium, I.sup.-                          26  iso-propyl                                                                              Ph--                                                                              7-(N)-N-methyl-morpholinium, I.sup.-                           27  iso-propyl                                                                              Ph--                                                                              7-(N)-N'-methylpiperazine                                      28  iso-propyl                                                                              Ph--                                                                              7-(N)-N'-dimethylpiperazinium, I.sup.-                         29  iso-propyl                                                                              Ph--                                                                              7-NH-CBZ                                                       30  iso-propyl                                                                              Ph--                                                                              7-NHC(O)C.sub.5 H.sub.11                                       31  iso-propyl                                                                              Ph--                                                                              7-NHC(O)CH.sub.2 Br                                            32  iso-propyl                                                                              Ph--                                                                              7-NH--C(NH)NH.sub.2                                            33  iso-propyl                                                                              Ph--                                                                              7-(2)-thiophene                                                34  iso-propyl                                                                              Ph--                                                                              8-methyl                                                       35  iso-propyl                                                                              Ph--                                                                              8-ethyl                                                        36  iso-propyl                                                                              Ph--                                                                              8-iso-propyl                                                   37  iso-propyl                                                                              Ph--                                                                              8-tert-butyl                                                   38  iso-propyl                                                                              Ph--                                                                              8-OH                                                           39  iso-propyl                                                                              Ph--                                                                              8-OCH.sub.3                                                    40  iso-propyl                                                                              Ph--                                                                              8-O(iso-propyl)                                                41  iso-propyl                                                                              Ph--                                                                              8-SCH.sub.3                                                    42  iso-propyl                                                                              Ph--                                                                              8-SOCH.sub.3                                                   43  iso-propyl                                                                              Ph--                                                                              8-SO.sub.2 CH.sub.3                                            4.4 iso-propyl                                                                              Ph--                                                                              8-SCH.sub.2 CH.sub.3                                           45  iso-propyl                                                                              Ph--                                                                              8-NH.sub.2                                                     46  iso-propyl                                                                              Ph--                                                                              8-NHOH                                                         47  iso-propyl                                                                              Ph--                                                                              8-NHCH.sub.3                                                   48  iso-propyl                                                                              Ph--                                                                              8-N(CH.sub.3).sub.2                                            49  iso-propyl                                                                              Ph--                                                                              8-N.sup.+ (CH.sub.3).sub.3, I.sup.-                            50  iso-propyl                                                                              Ph--                                                                              8-NHC(═O)CH.sub.3                                          51  iso-propyl                                                                              Ph--                                                                              8-N(CH.sub.2 CH.sub.3).sub.2                                   52  iso-propyl                                                                              Ph--                                                                              8-NMeCH.sub.2 CO.sub.2 H                                       53  iso-propyl                                                                              Ph--                                                                              8-N.sup.+ (Me).sub.2 CH.sub.2 CO.sub.2 H, I.sup.-              54  iso-propyl                                                                              Ph--                                                                              8-(N)-morpholine                                               55  iso-propyl                                                                              Ph--                                                                              8-(N)-azetidine                                                56  iso-propyl                                                                              Ph--                                                                              8-(N)-N-methylazetidinium, I.sup.-                             57  iso-propyl                                                                              Ph--                                                                              8-(N)-pyrrolidine                                              58  iso-propyl                                                                              Ph--                                                                              8-(N)-N-methyl-pyrrolidinium, I.sup.-                          59  iso-propyl                                                                              Ph--                                                                              8-(N)-N-methyl-morpholinium, I.sup.-                           60  iso-propyl                                                                              Ph--                                                                              8-(N)-N'-methylpiperazine                                      61  iso-propyl                                                                              Ph--                                                                              8-(N)-N'-dimethylpiperazinium, I.sup.-                         62  iso -propyl                                                                             Ph--                                                                              8-NH-CBZ                                                       63  iso-propyl                                                                              Ph--                                                                              8-NHC(O)C.sub.5 H.sub.11                                       64  iso-propyl                                                                              Ph--                                                                              8-NHC(O)CH.sub.2 Br                                            65  iso-propyl                                                                              Ph--                                                                              8-NH--C(NH)NH.sub.2                                            66  iso-propyl                                                                              Ph--                                                                              8-(2)-thiophene                                                67  iso-propyl                                                                              Ph--                                                                              9-methyl                                                       68  iso-propyl                                                                              Ph--                                                                              9-ethyl                                                        69  iso-propyl                                                                              Ph--                                                                              9-iso-propyl                                                   70  iso-propyl                                                                              Ph--                                                                              9-tert-butyl                                                   71  iso-propyl                                                                              Ph--                                                                              9-OH                                                           72  iso-propyl                                                                              Ph--                                                                              9-OCH.sub.3                                                    73  iso-propyl                                                                              Ph--                                                                              9-O(iso-propyl)                                                74  iso-propyl                                                                              Ph--                                                                              9-SCH.sub.3                                                    75  iso-propyl                                                                              Ph--                                                                              9-SOCH.sub.3                                                   76  iso-propyl                                                                              Ph--                                                                              9-SO.sub.2 CH.sub.3                                            77  iso-propyl                                                                              Ph--                                                                              9-SCH.sub.2 CH.sub.3                                           78  iso-propyl                                                                              Ph--                                                                              9-NH.sub.2                                                     79  iso-propyl                                                                              Ph--                                                                              9-NHOH                                                         80  iso-propyl                                                                              Ph--                                                                              9-NHCH.sub.3                                                   81  iso-propyl                                                                              Ph--                                                                              9-N(CH.sub.3).sub.2                                            82  iso-propyl                                                                              Ph--                                                                              9-N.sup.+ (CH.sub.3).sub.3, I.sup.-                            83  iso-propyl                                                                              Ph--                                                                              9-NHC(═O)CH.sub.3                                          84  iso-propyl                                                                              Ph--                                                                              9-N(CH.sub.2 CH.sub.3).sub.2                                   85  iso-propyl                                                                              Ph--                                                                              9-NMeCH.sub.2 CO.sub.2 H                                       86  iso-propyl                                                                              Ph--                                                                              9-N.sup.+ (Me).sub.2 CH.sub.2 CO.sub.2 H, I.sup.-              87  iso-propyl                                                                              Ph--                                                                              9-(N)-morpholine                                               88  iso-propyl                                                                              Ph--                                                                              9-(N)-azetidine                                                89  iso-propyl                                                                              Ph--                                                                              9-(N)-N-methylazetidinium, I.sup.-                             90  iso-propyl                                                                              Ph--                                                                              9-(N)-pyrrolidine                                              91  iso-propyl                                                                              Ph--                                                                              9-(N)-N-methyl-pyrrolidinium, I.sup.-                          92  iso-propyl                                                                              Ph--                                                                              9-(N)-N-methyl-morpholinium, I.sup.-                           93  iso-propyl                                                                              Ph--                                                                              9-(N)-N'-methylpiperazine                                      93  iso-propyl                                                                              Ph--                                                                              9-(N)-N'-dimethylpiperazinium, I.sup.-                         95  iso-propyl                                                                              Ph--                                                                              9-NH-CBZ                                                       96  iso-propyl                                                                              Ph--                                                                              9-NHC(O)C.sub.5 H.sub.11                                       97  iso-propyl                                                                              Ph--                                                                              9-NHC(O)CH.sub.2 Br                                            98  iso-propyl                                                                              Ph--                                                                              9-NH--C(NH)NH.sub.2                                            99  iso-propyl                                                                              Ph--                                                                              9-(2)-thiophene                                                100 iso-propyl                                                                              Ph--                                                                              7-OCH.sub.3, 8-OCH.sub.3                                       101 iso-propyl                                                                              Ph--                                                                              7-SCH.sub.3, 8-OCH.sub.3                                       102 iso-propyl                                                                              Ph--                                                                              7-SCH.sub.3, 8-SCH.sub.3                                       103 iso-propyl                                                                              Ph--                                                                              6-OCH.sub.3, 7-OCH.sub.3, 8-OCH.sub.3                   F101.007                                                                              01  iso-butyl                                                                               Ph--                                                                              7-methyl                                                       02  iso-butyl                                                                               Ph--                                                                              7-ethyl                                                        03  iso-butyl                                                                               Ph--                                                                              7-iso-propyl                                                   04  iso-butyl                                                                               Ph--                                                                              7-tert-butyl                                                   05  iso-butyl                                                                               Ph--                                                                              7-OH                                                           06  iso-butyl                                                                               Ph--                                                                              7-OCH.sub.3                                                    07  iso-butyl                                                                               Ph--                                                                              7-O(iso-propyl)                                                08  iso-butyl                                                                               Ph--                                                                              7-SCH.sub.3                                                    09  iso-butyl                                                                               Ph--                                                                              7-SOCH.sub.3                                                   10  iso-butyl                                                                               Ph--                                                                              7-SO.sub.2 CH.sub.3                                            11  iso-butyl                                                                               Ph--                                                                              7-SCH.sub.2 CH.sub.3                                           12  iso-butyl                                                                               Ph--                                                                              7-NH.sub.2                                                     13  iso-butyl                                                                               Ph--                                                                              7-NHOH                                                         14  iso-butyl                                                                               Ph--                                                                              7-NHCH.sub.3                                                   15  iso-butyl                                                                               Ph--                                                                              7-N(CH.sub.3).sub.2                                            16  iso-butyl                                                                               Ph--                                                                              7-N.sup.+ (CH.sub.3).sub.3, I.sup.-                            17  iso-butyl                                                                               Ph--                                                                              7-NHC(═O)CH.sub.3                                          18  iso-butyl                                                                               Ph--                                                                              7-N(CH.sub.2 CH.sub.3).sub.2                                   19  iso-butyl                                                                               Ph--                                                                              7-NMeCH.sub.2 CO.sub.2 H                                       20  iso-butyl                                                                               Ph--                                                                              7-N.sup.+ (Me).sub.2 CH.sub.2 CO.sub.2 H, I.sup.-              21  iso-butyl                                                                               Ph--                                                                              7-(N)-morpholine                                               22  iso-butyl                                                                               Ph--                                                                              7-(N)-azetidine                                                23  iso-butyl                                                                               Ph--                                                                              7-(N)-N-methylazetidinium, I.sup.-                             24  iso-butyl                                                                               Ph--                                                                              7-(N)-pyrrolidine                                              25  iso-butyl                                                                               Ph--                                                                              7-(N)-N-methyl-pyrrolidinium, I.sup.-                          26  iso-butyl                                                                               Ph--                                                                              7-(N)-N-methyl-morpholinium, I.sup.-                           27  iso-butyl                                                                               Ph--                                                                              7-(N)-N'-methylpiperazine                                      28  iso-butyl                                                                               Ph--                                                                              7-(N)-N'-dimethylpiperazinium, I.sup.-                         29  iso-butyl                                                                               Ph--                                                                              7-NH-CBZ                                                       30  iso-butyl                                                                               Ph--                                                                              7-NHC(O)C.sub.5 H.sub.11                                       31  iso-butyl                                                                               Ph--                                                                              7-NHC(O)CH.sub.2 Br                                            32  iso-butyl                                                                               Ph--                                                                              7-NH--C(NH)NH.sub.2                                            33  iso-butyl                                                                               Ph--                                                                              7-(2)-thiophene                                                34  iso-butyl                                                                               Ph--                                                                              8-methyl                                                       35  iso-butyl                                                                               Ph--                                                                              8-ethyl                                                        36  iso-butyl                                                                               Ph--                                                                              8-iso-propyl                                                   37  iso-butyl                                                                               Ph--                                                                              8-tert-butyl                                                   38  iso-butyl                                                                               Ph--                                                                              8-OH                                                           39  iso-butyl                                                                               Ph--                                                                              8-OCH.sub.3                                                    40  iso-butyl                                                                               Ph--                                                                              8-O(iso-propyl)                                                41  iso-butyl                                                                               Ph--                                                                              8-SCH.sub.3                                                    42  iso-butyl                                                                               Ph--                                                                              8-SOCH.sub.3                                                   43  iso-butyl                                                                               Ph--                                                                              8-SO.sub.2 CH.sub.3                                            44  iso-butyl                                                                               Ph--                                                                              8-SCH.sub.2 CH.sub.3                                           45  iso-butyl                                                                               Ph--                                                                              8-NH.sub.2                                                     46  iso-butyl                                                                               Ph--                                                                              8-NHOH                                                         47  iso-butyl                                                                               Ph--                                                                              8-NHCH.sub.3                                                   48  iso-butyl                                                                               Ph--                                                                              8-N(CH.sub.3).sub.2                                            49  iso-butyl                                                                               Ph--                                                                              8-N.sup.+ (CH.sub.3).sub.3, I.sup.-                            50  iso-butyl                                                                               Ph--                                                                              8-NHC(═O)CH.sub.3                                          51  iso-butyl                                                                               Ph--                                                                              8-N(CH.sub.2 CH.sub.3).sub.2                                   52  iso-butyl                                                                               Ph--                                                                              8-NMeCH.sub.2 CO.sub.2 H                                       53  iso-butyl                                                                               Ph--                                                                              8-N.sup.+ (Me).sub.2 CH.sub.2 CO.sub.2 H, I.sup.-              54  iso-butyl                                                                               Ph--                                                                              8-(N)-morpholine                                               55  iso-butyl                                                                               Ph--                                                                              8-(N)-azetidine                                                56  iso-butyl                                                                               Ph--                                                                              8-(N)-N-methylazetidinium, I.sup.-                             57  iso-butyl                                                                               Ph--                                                                              8-(N)-pyrrolidine                                              58  iso-butyl                                                                               Ph--                                                                              8-(N)-N-methyl-pyrrolidinium, I.sup.-                          59  iso-butyl                                                                               Ph--                                                                              8-(N)-N-methyl-morpholinium, I.sup.-                           60  iso-butyl                                                                               Ph--                                                                              8-(N)-N'-methylpiperazine                                      61  iso-butyl                                                                               Ph--                                                                              8-(N)-N'-dimethylpiperazinium, I.sup.-                         62  iso-butyl                                                                               Ph--                                                                              8-NH-CBZ                                                       63  iso-butyl                                                                               Ph--                                                                              8-NHC(O)C.sub.5 H.sub.11                                       64  iso-butyl                                                                               Ph--                                                                              8-NHC(O)CH.sub.2 Br                                            65  iso-butyl                                                                               Ph--                                                                              8-NH--C(NH)NH.sub.2                                            66  iso-butyl                                                                               Ph--                                                                              8-(2)-thiophene                                                67  iso-butyl                                                                               Ph--                                                                              9-methyl                                                       68  iso-butyl                                                                               Ph--                                                                              9-ethyl                                                        69  iso-butyl                                                                               Ph--                                                                              9-iso-propyl                                                   70  iso-butyl                                                                               Ph--                                                                              9-tert-butyl                                                   71  iso-butyl                                                                               Ph--                                                                              9-OH                                                           72  iso-butyl                                                                               Ph--                                                                              9-OCH.sub.3                                                    73  iso-butyl                                                                               Ph--                                                                              9-O(iso-propyl)                                                74  iso-butyl                                                                               Ph--                                                                              9-SCH.sub.3                                                    75  iso-butyl                                                                               Ph--                                                                              9-SOCH.sub.3                                                   76  iso-butyl                                                                               Ph--                                                                              9-SO.sub.2 CH.sub.3                                            77  iso-butyl                                                                               Ph--                                                                              9-SCH.sub.2 CH.sub.3                                           78  iso-butyl                                                                               Ph--                                                                              9-NH.sub.2                                                     79  iso-butyl                                                                               Ph--                                                                              9-NHOH                                                         80  iso-butyl                                                                               Ph--                                                                              9-NHCH.sub.3                                                   81  iso-butyl                                                                               Ph--                                                                              9-N(CH.sub.3).sub.2                                            82  iso-butyl                                                                               Ph--                                                                              9-N.sup.+ (CH.sub.3).sub.3, I.sup.-                            83  iso-butyl                                                                               Ph--                                                                              9-NHC(═O)CH.sub.3                                          84  iso-butyl                                                                               Ph--                                                                              9-N(CH.sub.2 CH.sub.3).sub.2                                   85  iso-butyl                                                                               Ph--                                                                              9-NMeCH.sub.2 CO.sub.2 H                                       86  iso-butyl                                                                               Ph--                                                                              9-N.sup.+ (Me).sub.2 CH.sub.2 CO.sub.2 H, I.sup.-              87  iso-butyl                                                                               Ph--                                                                              9-(N)-morpholine                                               88  iso-butyl                                                                               Ph--                                                                              9-(N)-azetidine                                                89  iso-butyl                                                                               Ph--                                                                              9-(N)-N-methylazetidinium, I.sup.-                             90  iso-butyl                                                                               Ph--                                                                              9-(N)-pyrrolidine                                              91  iso-butyl                                                                               Ph--                                                                              9-(N)-N-methyl-pyrrolidinium, I.sup.-                          92  iso-butyl                                                                               Ph--                                                                              9-(N)-N-methyl-morpholinium, I.sup.-                           93  iso-butyl                                                                               Ph--                                                                              9-(N)-N'-methylpiperazine                                      93  iso-butyl                                                                               Ph--                                                                              9-(N)-N'-dimethylpiperazinium, I.sup.-                         95  iso-butyl                                                                               Ph--                                                                              9-NH-CBZ                                                       96  iso-butyl                                                                               Ph--                                                                              9-NHC(O)C.sub.5 H.sub.11                                       97  iso-butyl                                                                               Ph--                                                                              9-NHC(O)CH.sub.2 Br                                            98  iso-butyl                                                                               Ph--                                                                              9-NH--C(NH)NH.sub.2                                            99  iso-butyl                                                                               Ph--                                                                              9-(2)-thiophene                                                100 iso-butyl                                                                               Ph--                                                                              7-OCH.sub.3, 8-OCH.sub.3                                       101 iso-butyl                                                                               Ph--                                                                              7-SCH.sub.3, 8-OCH.sub.3                                       102 iso-butyl                                                                               Ph--                                                                              7-SCH.sub.3, 8-SCH.sub.3                                       103 iso-butyl                                                                               Ph--                                                                              6-OCH.sub.3, 7-OCH.sub.3, 8-OCH.sub.3                   F101.008                                                                              01  iso-pentyl                                                                              Ph--                                                                              7-methyl                                                       02  iso-pentyl                                                                              Ph--                                                                              7-ethyl                                                        03  iso-pentyl                                                                              Ph--                                                                              7-iso-propyl                                                   04  iso-pentyl                                                                              Ph--                                                                              7-tert-butyl                                                   05  iso-pentyl                                                                              Ph--                                                                              7-OH                                                           06  iso-pentyl                                                                              Ph--                                                                              7-OCH.sub.3                                                    07  iso-pentyl                                                                              Ph--                                                                              7-O(iso-propyl)                                                08  iso-pentyl                                                                              Ph--                                                                              7-SCH.sub.3                                                    09  iso-pentyl                                                                              Ph--                                                                              7-SOCH.sub.3                                                   10  iso-pentyl                                                                              Ph--                                                                              7-SO.sub.2 CH.sub.3                                            11  iso-pentyl                                                                              Ph--                                                                              7-SCH.sub.2 CH.sub.3                                           12  iso-pentyl                                                                              Ph--                                                                              7-NH.sub.2                                                     13  iso-pentyl                                                                              Ph--                                                                              7-NHOH                                                         14  iso-pentyl                                                                              Ph--                                                                              7-NHCH.sub.3                                                   15  iso-pentyl                                                                              Ph--                                                                              7-N(CH.sub.3).sub.2                                            16  iso-pentyl                                                                              Ph--                                                                              7-N.sup.+ (CH.sub.3).sub.3, I.sup.-                            17  iso-pentyl                                                                              Ph--                                                                              7-NHC(═O)CH.sub.3                                          18  iso-pentyl                                                                              Ph--                                                                              7-N(CH.sub.2 CH.sub.3).sub.2                                   19  iso-pentyl                                                                              Ph--                                                                              7-NMeCH.sub.2 CO.sub.2 H                                       20  iso-pentyl                                                                              Ph--                                                                              7-N.sup.+ (Me).sub.2 CH.sub.2 CO.sub.2 H, I.sup.-              21  iso-pentyl                                                                              Ph--                                                                              7-(N)-morpholine                                               22  iso-pentyl                                                                              Ph--                                                                              7-(N)-azetidine                                                23  iso-pentyl                                                                              Ph--                                                                              7-(N)-N-methylazetidinium, I.sup.-                             24  iso-pentyl                                                                              Ph--                                                                              7-(N)-pyrrolidine                                              25  iso-pentyl                                                                              Ph--                                                                              7-(N)-N-methyl-pyrrolidinium, I.sup.-                          26  iso-pentyl                                                                              Ph--                                                                              7-(N)-N-methyl-morpholinium, I.sup.-                           27  iso-pentyl                                                                              Ph--                                                                              7-(N)-N'-methylpiperazine                                      28  isa-pentyl                                                                              Ph--                                                                              7-(N)-N'-dimethylpiperazinium, I.sup.-                         29  iso-pentyl                                                                              Ph--                                                                              7-NH-CBZ                                                       30  iso-pentyl                                                                              Ph--                                                                              7-NHC(O)C.sub.5 H.sub.11                                       31  isa-pentyl                                                                              Ph--                                                                              7-NHC(O)CH.sub.2 Br                                            32  iso-pentyl                                                                              Ph--                                                                              7-NH--C(NH)NH.sub.2                                            33  iso-pentyl                                                                              Ph--                                                                              7-(2)-thiophene                                                34  iso-pentyl                                                                              Ph--                                                                              8-methyl                                                       35  iso-pentyl                                                                              Ph--                                                                              8-ethyl                                                        36  iso-pentyl                                                                              Ph--                                                                              8-iso-propyl                                                   37  iso-pentyl                                                                              Ph--                                                                              8-tert-butyl                                                   38  iso-pentyl                                                                              Ph--                                                                              8-OH                                                           39  iso-pentyl                                                                              Ph--                                                                              8-OCH.sub.3                                                    40  iso-pentyl                                                                              Ph--                                                                              8-O(iso-propyl)                                                41  iso-pentyl                                                                              Ph--                                                                              8-SCH.sub.3                                                    42  iso-pentyl                                                                              Ph--                                                                              8-SOCH.sub.3                                                   43  iso-pentyl                                                                              Ph--                                                                              8-SO.sub.2 CH.sub.3                                            44  iso-pentyl                                                                              Ph--                                                                              8-SCH.sub.2 CH.sub.3                                           45  iso-pentyl                                                                              Ph--                                                                              8-NH.sub.2                                                     46  iso-pentyl                                                                              Ph--                                                                              8-NHOH                                                         47  iso-pentyl                                                                              Ph--                                                                              8-NHCH.sub.3                                                   48  iso-pentyl                                                                              Ph--                                                                              8-N(CH.sub.3).sub.2                                            49  iso-pentyl                                                                              Ph--                                                                              8-N.sup.+ (CH.sub.3).sub.3, I.sup.-                            50  iso-pentyl                                                                              Ph--                                                                              8-NHC(═O)CH.sub.3                                          51  iso-pentyl                                                                              Ph--                                                                              8-N(CH.sub.2 CH.sub.3).sub.2                                   52  iso-pentyl                                                                              Ph--                                                                              8-NMeCH.sub.2 CO.sub.2 H                                       53  iso-pentyl                                                                              Ph--                                                                              8-N.sup.+ (Me).sub.2 CH.sub.2 CO.sub.2 H, I.sup.-              54  iso-pentyl                                                                              Ph--                                                                              8-(N)-morpholine                                               55  iso-pentyl                                                                              Ph--                                                                              8-(N)-azetidine                                                56  iso-pentyl                                                                              Ph--                                                                              8-(N)-N-methylazetidinium, I.sup.-                             57  iso-pentyl                                                                              Ph--                                                                              8-(N)-pyrrolidine                                              58  iso-pentyl                                                                              Ph--                                                                              8-(N)-N-methyl-pyrrolidinium, I.sup.-                          59  iso-pentyl                                                                              Ph--                                                                              8-(N)-N-methyl-morpholinium, I.sup.-                           60  iso-pentyl                                                                              Ph--                                                                              8-(N)-N'-methylpiperazine                                      61  iso-pentyl                                                                              Ph--                                                                              8-(N)-N'-dimethylpiperazinium, I.sup.-                         62  iso-pentyl                                                                              Ph--                                                                              8-NH-CBZ                                                       63  iso-pentyl                                                                              Ph--                                                                              8-NHC(O)C.sub.5 H.sub.11                                       64  iso-pentyl                                                                              Ph--                                                                              8-NHC(O)CH.sub.2 Br                                            65  iso-pentyl                                                                              Ph--                                                                              8-NH--C(NH)NH.sub.2                                            66  iso-pentyl                                                                              Ph--                                                                              8-(2)-thiophene                                                67  iso-pentyl                                                                              Ph--                                                                              9-methyl                                                       68  iso-pentyl                                                                              Ph--                                                                              9-ethyl                                                        69  iso-pentyl                                                                              Ph--                                                                              9-iso-propyl                                                   70  iso-pentyl                                                                              Ph--                                                                              9-tert-butyl                                                   71  iso-pentyl                                                                              Ph--                                                                              9-OH                                                           72  iso-pentyl                                                                              Ph--                                                                              9-OCH.sub.3                                                    73  iso-pentyl                                                                              Ph--                                                                              9-O(iso-propyl)                                                74  iso-pentyl                                                                              Ph--                                                                              9-SCH.sub.3                                                    75  iso-pentyl                                                                              Ph--                                                                              9-SOCH.sub.3                                                   76  iso-pentyl                                                                              Ph--                                                                              9-SO.sub.2 CH.sub.3                                            77  iso-pentyl                                                                              Ph--                                                                              9-SCH.sub.2 CH.sub.3                                           78  iso-pentyl                                                                              Ph--                                                                              9-NH.sub.2                                                     79  iso-pentyl                                                                              Ph--                                                                              9-NHOH                                                         80  iso-pentyl                                                                              Ph--                                                                              9-NHCH.sub.3                                                   81  iso-pentyl                                                                              Ph--                                                                              9-N(CH.sub.3).sub.2                                            82  iso-pentyl                                                                              Ph--                                                                              9-N.sup.+ (CH.sub.3).sub.3, I.sup.-                            83  iso-pentyl                                                                              Ph--                                                                              9-NHC(═O)CH.sub.3                                          84  iso-pentyl                                                                              Ph--                                                                              9-N(CH.sub.2 CH.sub.3).sub.2                                   85  iso-pentyl                                                                              Ph--                                                                              9-NMeCH.sub.2 CO.sub.2 H                                       86  iso-pentyl                                                                              Ph--                                                                              9-N.sup.+ (Me).sub.2 CH.sub.2 CO.sub.2 H, I.sup.-              87  iso-pentyl                                                                              Ph--                                                                              9-(N)-morpholine                                               88  isa-pentyl                                                                              Ph--                                                                              9-(N)-azetidine                                                89  iso-pentyl                                                                              Ph--                                                                              9-(N)-N-methylazetidinium, I.sup.-                             90  iso-pentyl                                                                              Ph--                                                                              9-(N)-pyrrolidine                                              91  iso-pentyl                                                                              Ph--                                                                              9-(N)-N-methyl-pyrrolidinium, I.sup.-                          92  iso-pentyl                                                                              Ph--                                                                              9-(N)-N-methyl-morpholinium, I.sup.-                           93  iso-pentyl                                                                              Ph--                                                                              9-(N)-N'-methylpiperazine                                      93  iso-pentyl                                                                              Ph--                                                                              9-(N)-N'-dimethylpiperazinium, I.sup.-                         95  iso-pentyl                                                                              Ph--                                                                              9-NH-CBZ                                                       96  iso-pentyl                                                                              Ph--                                                                              9-NHC(O)C.sub.5 H.sub.11                                       97  iso-pentyl                                                                              Ph--                                                                              9-NHC(O)CH.sub.2 Br                                            98  iso-pentyl                                                                              Ph--                                                                              9-NH--C(NH)NH.sub.2                                            99  iso-pentyl                                                                              Ph--                                                                              9-(2)-thiophene                                                100 iso-pentyl                                                                              Ph--                                                                              7-OCH.sub.3, 8-OCH.sub.3                                       101 iso-pentyl                                                                              Ph--                                                                              7-SCH.sub.3, 8-OCH.sub.3                                       102 iso-pentyl                                                                              Ph--                                                                              7-SCH.sub.3, 8-SCH.sub.3                                       103 iso-pentyl                                                                              Ph--                                                                              6-OCH.sub.3, 7-OCH.sub.3, 8-OCH.sub.3                   F101.009                                                                              01  CH.sub.2 C(═O)C.sub.2 H.sub.5                                                       Ph--                                                                              7-methyl                                                       02  CH.sub.2 C(═O)C.sub.2 H.sub.5                                                       Ph--                                                                              7-ethyl                                                        03  CH.sub.2 C(═O)C.sub.2 H.sub.5                                                       Ph--                                                                              7-iso-propyl                                                   04  CH.sub.2 C(═O)C.sub.2 H.sub.5                                                       Ph--                                                                              7-tert-butyl                                                   05  CH.sub.2 C(═O)C.sub.2 H.sub.5                                                       Ph--                                                                              7-OH                                                           06  CH.sub.2 C(═O)C.sub.2 H.sub.5                                                       Ph--                                                                              7-OCH.sub.3                                                    07  CH.sub.2 C(═O)C.sub.2 H.sub.5                                                       Ph--                                                                              7-O(iso-propyl)                                                08  CH.sub.2 C(═O)C.sub.2 H.sub.5                                                       Ph--                                                                              7-SCH.sub.3                                                    09  CH.sub.2 C(═O)C.sub.2 H.sub.5                                                       Ph--                                                                              7-SOCH.sub.3                                                   10  CH.sub.2 C(═O)C.sub.2 H.sub.5                                                       Ph--                                                                              7-SO.sub.2 CH.sub.3                                            11  CH.sub.2 C(═O)C.sub.2 H.sub.5                                                       Ph--                                                                              7-SCH.sub.2 CH.sub.3                                           12  CH.sub.2 C(═O)C.sub.2 H.sub.5                                                       Ph--                                                                              7-NH.sub.2                                                     13  CH.sub.2 C(═O)C.sub.2 H.sub.5                                                       Ph--                                                                              7-NHOH                                                         14  CH.sub.2 C(═O)C.sub.2 H.sub.5                                                       Ph--                                                                              7-NHCH.sub.3                                                   15  CH.sub.2 C(═O)C.sub.2 H.sub.5                                                       Ph--                                                                              7-N(CH.sub.3).sub.2                                            16  CH.sub.2 C(═O)C.sub.2 H.sub.5                                                       Ph--                                                                              7-N.sup.+ (CH.sub.3).sub.3, I.sup.-                            17  CH.sub.2 C(═O)C.sub.2 H.sub.5                                                       Ph--                                                                              7-NHC(═O)CH.sub.3                                          18  CH.sub.2 C(═O)C.sub.2 H.sub.5                                                       Ph--                                                                              7-N(CH.sub.2 CH.sub.3).sub.2                                   19  CH.sub.2 C(═O)C.sub.2 H.sub.5                                                       Ph--                                                                              7-NMeCH.sub.2 CO.sub.2 H                                       20  CH.sub.2 C(═O)C.sub.2 H.sub.5                                                       Ph--                                                                              7-N.sup.+ (Me).sub.2 CH.sub.2 CO.sub.2 H, I.sup.-              21  CH.sub.2 C(═O)C.sub.2 H.sub.5                                                       Ph--                                                                              7-(N)-morpholine                                               22  CH.sub.2 C(═O)C.sub.2 H.sub.5                                                       Ph--                                                                              7-(N)-azetidine                                                23  CH.sub.2 C(═O)C.sub.2 H.sub.5                                                       Ph--                                                                              7-(N)-N-methylazetidinium, I.sup.-                             24  CH.sub.2 C(═O)C.sub.2 H.sub.5                                                       Ph--                                                                              7-(N)-pyrrolidine                                              25  CH.sub.2 C(═O)C.sub.2 H.sub.5                                                       Ph--                                                                              7-(N)-N-methyl-pyrrolidinium, I.sup.-                          26  CH.sub.2 C(═O)C.sub.2 H.sub.5                                                       Ph--                                                                              7-(N)-N-methyl-morpholinium, I.sup.-                           27  CH.sub.2 C(═O)C.sub.2 H.sub.5                                                       Ph--                                                                              7-(N)-N'-methylpiperazine                                      28  CH.sub.2 C(═O)C.sub.2 H.sub.5                                                       Ph--                                                                              7-(N)-N'-dimethylpiperazinium, I.sup.-                         29  CH.sub.2 C(═O)C.sub.2 H.sub.5                                                       Ph--                                                                              7-NH-CBZ                                                       30  CH.sub.2 C(═O)C.sub.2 H.sub.5                                                       Ph--                                                                              7-NHC(O)C.sub.5 H.sub.11                                       31  CH.sub.2 C(═O)C.sub.2 H.sub.5                                                       Ph--                                                                              7-NHC(O)CH.sub.2 Br                                            32  CH.sub.2 C(═O)C.sub.2 H.sub.5                                                       Ph--                                                                              7-NH--C(NH)NH.sub.2                                            33  CH.sub.2 C(═O)C.sub.2 H.sub.5                                                       Ph--                                                                              7-(2)-thiophene                                                34  CH.sub.2 C(═O)C.sub.2 H.sub.5                                                       Ph--                                                                              8-methyl                                                       35  CH.sub.2 C(═O)C.sub.2 H.sub.5                                                       Ph--                                                                              8-ethyl                                                        36  CH.sub.2 C(═O)C.sub.2 H.sub.5                                                       Ph--                                                                              8-iso-propyl                                                   37  CH.sub.2 C(═O)C.sub.2 H.sub.5                                                       Ph--                                                                              8-tert-butyl                                                   38  CH.sub.2 C(═O)C.sub.2 H.sub.5                                                       Ph--                                                                              8-OH                                                           39  CH.sub.2 C(═O)C.sub.2 H.sub.5                                                       Ph--                                                                              8-OCH.sub.3                                                    40  CH.sub.2 C(═O)C.sub.2 H.sub.5                                                       Ph--                                                                              8-O(iso-propyl)                                                41  CH.sub.2 C(═O)C.sub.2 H.sub.5                                                       Ph--                                                                              8-SCH.sub.3                                                    42  CH.sub.2 C(═O)C.sub.2 H.sub.5                                                       Ph--                                                                              8-SOCH.sub.3                                                   43  CH.sub.2 C(═O)C.sub.2 H.sub.5                                                       Ph--                                                                              8-SO.sub.2 CH.sub.3                                            44  CH.sub.2 C(═O)C.sub.2 H.sub.5                                                       Ph--                                                                              8-SCH.sub.2 CH.sub.3                                           45  CH.sub.2 C(═O)C.sub.2 H.sub.5                                                       Ph--                                                                              8-NH.sub.2                                                     46  CH.sub.2 C(═O)C.sub.2 H.sub.5                                                       Ph--                                                                              8-NHOH                                                         47  CH.sub.2 C(═O)C.sub.2 H.sub.5                                                       Ph--                                                                              8-NHCH.sub.3                                                   48  CH.sub.2 C(═O)C.sub.2 H.sub.5                                                       Ph--                                                                              8-N(CH.sub.3).sub.2                                            49  CH.sub.2 C(═O)C.sub.2 H.sub.5                                                       Ph--                                                                              8-N.sup.+ (CH.sub.3).sub.3, I.sup.-                            50  CH.sub.2 C(═O)C.sub.2 H.sub.5                                                       Ph--                                                                              8-NHC(═O)CH.sub.3                                          51  CH.sub.2 C(═O)C.sub.2 H.sub.5                                                       Ph--                                                                              8-N(CH.sub.2 CH.sub.3).sub.2                                   52  CH.sub.2 C(═O)C.sub.2 H.sub.5                                                       Ph--                                                                              8-NMeCH.sub.2 CO.sub.2 H                                       53  CH.sub.2 C(═O)C.sub.2 H.sub.5                                                       Ph--                                                                              8-N.sup.+ (Me).sub.2 CH.sub.2 CO.sub.2 H, I.sup.-              54  CH.sub.2 C(═O)C.sub.2 H.sub.5                                                       Ph--                                                                              8-(N)-morpholine                                               55  CH.sub.2 C(═O)C.sub.2 H.sub.5                                                       Ph--                                                                              8-(N)-azetidine                                                56  CH.sub.2 C(═O)C.sub.2 H.sub.5                                                       Ph--                                                                              8-(N)-N-methylazetidinium, I.sup.-                             57  CH.sub.2 C(═O)C.sub.2 H.sub.5                                                       Ph--                                                                              8-(N)-pyrrolidine                                              58  CH.sub.2 C(═O)C.sub.2 H.sub.5                                                       Ph--                                                                              8-(N)-N-methyl-pyrrolidinium, I.sup.-                          59  CH.sub.2 C(═O)C.sub.2 H.sub.5                                                       Ph--                                                                              8-(N)-N-methyl-morpholinium, I.sup.-                           60  CH.sub.2 C(═O)C.sub.2 H.sub.5                                                       Ph--                                                                              8-(N)-N'-methylpiperazine                                      61  CH.sub.2 C(═O)C.sub.2 H.sub.5                                                       Ph--                                                                              8-(N)-N'-dimethylpiperazinium, I.sup.-                         62  CH.sub.2 C(═O)C.sub.2 H.sub.5                                                       Ph--                                                                              8-NH-CBZ                                                       63  CH.sub.2 C(═O)C.sub.2 H.sub.5                                                       Ph--                                                                              8-NHC(O)C.sub.5 H.sub.11                                       64  CH.sub.2 C(═O)C.sub.2 H.sub.5                                                       Ph--                                                                              8-NHC(O)CH.sub.2 Br                                            65  CH.sub.2 C(═O)C.sub.2 H.sub.5                                                       Ph--                                                                              8-NH--C(NH)NH.sub.2                                            66  CH.sub.2 C(═O)C.sub.2 H.sub.5                                                       Ph--                                                                              8-(2)-thiophene                                                67  CH.sub.2 C(═O)C.sub.2 H.sub.5                                                       Ph--                                                                              9-methyl                                                       68  CH.sub.2 C(═O)C.sub.2 H.sub.5                                                       Ph--                                                                              9-ethyl                                                        69  CH.sub.2 C(═O)C.sub.2 H.sub.5                                                       Ph--                                                                              9-iso-propyl                                                   70  CH.sub.2 C(═O)C.sub.2 H.sub.5                                                       Ph--                                                                              9-tert-butyl                                                   71  CH.sub.2 C(═O)C.sub.2 H.sub.5                                                       Ph--                                                                              9-OH                                                           72  CH.sub.2 C(═O)C.sub.2 H.sub.5                                                       Ph--                                                                              9-OCH.sub.3                                                    73  CH.sub.2 C(═O)C.sub.2 H.sub.5                                                       Ph--                                                                              9-O(iso-propyl)                                                74  CH.sub.2 C(═O)C.sub.2 H.sub.5                                                       Ph--                                                                              9-SCH.sub.3                                                    75  CH.sub.2 C(═O)C.sub.2 H.sub.5                                                       Ph--                                                                              9-SOCH.sub.3                                                   76  CH.sub.2 C(═O)C.sub.2 H.sub.5                                                       Ph--                                                                              9-SO.sub.2 CH.sub.3                                            77  CH.sub.2 C(═O)C.sub.2 H.sub.5                                                       Ph--                                                                              9-SCH.sub.2 CH.sub.3                                           78  CH.sub.2 C(═O)C.sub.2 H.sub.5                                                       Ph--                                                                              9-NH.sub.2                                                     79  CH.sub.2 C(═O)C.sub.2 H.sub.5                                                       Ph--                                                                              9-NHOH                                                         80  CH.sub.2 C(═O)C.sub.2 H.sub.5                                                       Ph--                                                                              9-NHCH.sub.3                                                   81  CH.sub.2 C(═O)C.sub.2 H.sub.5                                                       Ph--                                                                              9-N(CH.sub.3).sub.2                                            82  CH.sub.2 C(═O)C.sub.2 H.sub.5                                                       Ph--                                                                              9-N.sup.+ (CH.sub.3).sub.3, I.sup.-                            83  CH.sub.2 C(═O)C.sub.2 H.sub.5                                                       Ph--                                                                              9-NHC(═O)CH.sub.3                                          84  CH.sub.2 C(═O)C.sub.2 H.sub.5                                                       Ph--                                                                              9-N(CH.sub.2 CH.sub.3).sub.2                                   85  CH.sub.2 C(═O)C.sub.2 H.sub.5                                                       Ph--                                                                              9-NMeCH.sub.2 CO.sub.2 H                                       86  CH.sub.2 C(═O)C.sub.2 H.sub.5                                                       Ph--                                                                              9-N.sup.+ (Me).sub.2 CH.sub.2 CO.sub.2 H, I.sup.-              87  CH.sub.2 C(═O)C.sub.2 H.sub.5                                                       Ph--                                                                              9-(N)-morpholine                                               88  CH.sub.2 C(═O)C.sub.2 H.sub.5                                                       Ph--                                                                              9-(N)-azetidine                                                89  CH.sub.2 C(═O)C.sub.2 H.sub.5                                                       Ph--                                                                              9-(N)-N-methylazetidinium, I.sup.-                             90  CH.sub.2 C(═O)C.sub.2 H.sub.5                                                       Ph--                                                                              9-(N)-pyrrolidine                                              91  CH.sub.2 C(═O)C.sub.2 H.sub.5                                                       Ph--                                                                              9-(N)-N-methyl-pyrrolidinium, I.sup.-                          92  CH.sub.2 C(═O)C.sub.2 H.sub.5                                                       Ph--                                                                              9-(N)-N-methyl-morpholinium, I.sup.-                           93  CH.sub.2 C(═O)C.sub.2 H.sub.5                                                       Ph--                                                                              9-(N)-N'-methylpiperazine                                      93  CH.sub.2 C(═O)C.sub.2 H.sub.5                                                       Ph--                                                                              9-(N)-N'-dimethylpiperazinium, I.sup.-                         95  CH.sub.2 C(═O)C.sub.2 H.sub.5                                                       Ph--                                                                              9-NH-CBZ                                                       96  CH.sub.2 C(═O)C.sub.2 H.sub.5                                                       Ph--                                                                              9-NHC(O)C.sub.5 H.sub.11                                       97  CH.sub.2 C(═O)C.sub.2 H.sub.5                                                       Ph--                                                                              9-NHC(O)CH.sub.2 Br                                            98  CH.sub.2 C(═O)C.sub.2 H.sub.5                                                       Ph--                                                                              9-NH--C(NH)NH.sub.2                                            99  CH.sub.2 C(═O)C.sub.2 H.sub.5                                                       Ph--                                                                              9-(2)-thiophene                                                100 CH.sub.2 C(═O)C.sub.2 H.sub.5                                                       Ph--                                                                              7-OCH.sub.3, 8-OCH.sub.3                                       101 CH.sub.2 C(═O)C.sub.2 H.sub.5                                                       Ph--                                                                              7-SCH.sub.3, 8-OCH.sub.3                                       102 CH.sub.2 C(═O)C.sub.2 H.sub.5                                                       Ph--                                                                              7-SCH.sub.3, 8-SCH.sub.3                                       103 CH.sub.2 C(═O)C.sub.2 H.sub.5                                                       Ph--                                                                              6-OCH.sub.3, 7-OCH.sub.3, 8-OCH.sub.3                   F101.010                                                                              01  CH.sub.2 OC.sub.2 H.sub.5                                                               Ph--                                                                              7-methyl                                                       02  CH.sub.2 OC.sub.2 H.sub.5                                                               Ph--                                                                              7-ethyl                                                        03  CH.sub.2 OC.sub.2 H.sub.5                                                               Ph--                                                                              7-iso-propyl                                                   04  CH.sub.2 OC.sub.2 H.sub.5                                                               Ph--                                                                              7-tert-butyl                                                   05  CH.sub.2 OC.sub.2 H.sub.5                                                               Ph--                                                                              7-OH                                                           06  CH.sub.2 OC.sub.2 H.sub.5                                                               Ph--                                                                              7-OCH.sub.3                                                    07  CH.sub.2 OC.sub.2 H.sub.5                                                               Ph--                                                                              7-O(iso-propyl)                                                08  CH.sub.2 OC.sub.2 H.sub.5                                                               Ph--                                                                              7-SCH.sub.3                                                    09  CH.sub.2 OC.sub.2 H.sub.5                                                               Ph--                                                                              7-SOCH.sub.3                                                   10  CH.sub.2 OC.sub.2 H.sub.5                                                               Ph--                                                                              7-SO.sub.2 CH.sub.3                                            11  CH.sub.2 OC.sub.2 H.sub.5                                                               Ph--                                                                              7-SCH.sub.2 CH.sub.3                                           12  CH.sub.2 OC.sub.2 H.sub.5                                                               Ph--                                                                              7-NH.sub.2                                                     13  CH.sub.2 OC.sub.2 H.sub.5                                                               Ph--                                                                              7-NHOH                                                         14  CH.sub.2 OC.sub.2 H.sub.5                                                               Ph--                                                                              7-NHCH.sub.3                                                   15  CH.sub.2 OC.sub.2 H.sub.5                                                               Ph--                                                                              7-N(CH.sub.3).sub.2                                            16  CH.sub.2 OC.sub.2 H.sub.5                                                               Ph--                                                                              7-N.sup.+ (CH.sub.3).sub.3, I.sup.-                            17  CH.sub.2 OC.sub.2 H.sub.5                                                               Ph--                                                                              7-NHC(═O)CH.sub.3                                          18  CH.sub.2 OC.sub.2 H.sub.5                                                               Ph--                                                                              7-N(CH.sub.2 CH.sub.3).sub.2                                   19  CH.sub.2 OC.sub.2 H.sub.5                                                               Ph--                                                                              7-NMeCH.sub.2 CO.sub.2 H                                       20  CH.sub.2 OC.sub.2 H.sub.5                                                               Ph--                                                                              7-N.sup.+ (Me).sub.2 CH.sub.2 CO.sub.2 H, I.sup.-              21  CH.sub.2 OC.sub.2 H.sub.5                                                               Ph--                                                                              7-(N)-morpholine                                               22  CH.sub.2 OC.sub.2 H.sub.5                                                               Ph--                                                                              7-(N)-azetidine                                                23  CH.sub.2 OC.sub.2 H.sub.5                                                               Ph--                                                                              7-(N)-N-methylazetidinium, I.sup.-                             24  CH.sub.2 OC.sub.2 H.sub.5                                                               Ph--                                                                              7-(N)-pyrrolidine                                              25  CH.sub.2 OC.sub.2 H.sub.5                                                               Ph--                                                                              7-(N)-N-methyl-pyrrolidinium, I.sup.-                          26  CH.sub.2 OC.sub.2 H.sub.5                                                               Ph--                                                                              7-(N)-N-methyl-morpholinium, I.sup.-                           27  CH.sub.2 OC.sub.2 H.sub.5                                                               Ph--                                                                              7-(N)-N'-methylpiperazine                                      28  CH.sub.2 OC.sub.2 H.sub.5                                                               Ph--                                                                              7-(N)-N'-diinethylpiperazinium, I.sup.-                        29  CH.sub.2 OC.sub.2 H.sub.5                                                               Ph--                                                                              7-NH-CBZ                                                       30  CH.sub.2 OC.sub.2 H.sub.5                                                               Ph--                                                                              7-NHC(O)C.sub.5 H.sub.11                                       31  CH.sub.2 OC.sub.2 H.sub.5                                                               Ph--                                                                              7-NHC(O)CH.sub.2 Br                                            32  CH.sub.2 OC.sub.2 H.sub.5                                                               Ph--                                                                              7-NH--C(NH)NH.sub.2                                            33  CH.sub.2 OC.sub.2 H.sub.5                                                               Ph--                                                                              7-(2)-thiophene                                                34  CH.sub.2 OC.sub.2 H.sub.5                                                               Ph--                                                                              8-methyl                                                       35  CH.sub.2 OC.sub.2 H.sub.5                                                               Ph--                                                                              8-ethyl                                                        36  CH.sub.2 OC.sub.2 H.sub.5                                                               Ph--                                                                              8-iso-propyl                                                   37  CH.sub.2 OC.sub.2 H.sub.5                                                               Ph--                                                                              8-tert-butyl                                                   38  CH.sub.2 OC.sub.2 H.sub.5                                                               Ph--                                                                              8-OH                                                           39  CH.sub.2 OC.sub.2 H.sub.5                                                               Ph--                                                                              8-OCH.sub.3                                                    40  CH.sub.2 OC.sub.2 H.sub.5                                                               Ph--                                                                              8-O(iso-propyl)                                                41  CH.sub.2 OC.sub.2 H.sub.5                                                               Ph--                                                                              8-SCH.sub.3                                                    42  CH.sub.2 OC.sub.2 H.sub.5                                                               Ph--                                                                              8-SOCH.sub.3                                                   43  CH.sub.2 OC.sub.2 H.sub.5                                                               Ph--                                                                              8-SO.sub.2 CH.sub.3                                            44  CH.sub.2 OC.sub.2 H.sub.5                                                               Ph--                                                                              8-SCH.sub.2 CH.sub.3                                           45  CH.sub.2 OC.sub.2 H.sub.5                                                               Ph--                                                                              8-NH.sub.2                                                     46  CH.sub.2 OC.sub.2 H.sub.5                                                               Ph--                                                                              8-NHOH                                                         47  CH.sub.2 OC.sub.2 H.sub.5                                                               Ph--                                                                              8-NHCH.sub.3                                                   48  CH.sub.2 OC.sub.2 H.sub.5                                                               Ph--                                                                              8-N(CH.sub.3).sub.2                                            49  CH.sub.2 OC.sub.2 H.sub.5                                                               Ph--                                                                              8-N.sup.+ (CH.sub.3).sub.3, I.sup.-                            50  CH.sub.2 OC.sub.2 H.sub.5                                                               Ph--                                                                              8-NHC(═O)CH.sub.3                                          51  CH.sub.2 OC.sub.2 H.sub.5                                                               Ph--                                                                              8-N(CH.sub.2 CH.sub.3).sub.2                                   52  CH.sub.2 OC.sub.2 H.sub.5                                                               Ph--                                                                              8-NMeCH.sub.2 CO.sub.2 H                                       53  CH.sub.2 OC.sub.2 H.sub.5                                                               Ph--                                                                              8-N.sup.+ (Me).sub.2 CH.sub.2 CO.sub.2 H, I.sup.-              54  CH.sub.2 OC.sub.2 H.sub.5                                                               Ph--                                                                              8-(N)-morpholine                                               55  CH.sub.2 OC.sub.2 H.sub.5                                                               Ph--                                                                              8-(N)-azetidine                                                56  CH.sub.2 OC.sub.2 H.sub.5                                                               Ph--                                                                              8-(N)-N-methylazetidinium, I.sup.-                             57  CH.sub.2 OC.sub.2 H.sub.5                                                               Ph--                                                                              8-(N)-pyrrolidine                                              58  CH.sub.2 OC.sub.2 H.sub.5                                                               Ph--                                                                              8-(N)-N-methyl-pyrrolidinium, I.sup.-                          59  CH.sub.2 OC.sub.2 H.sub.5                                                               Ph--                                                                              8-(N)-N-methyl-morpholinium1 I.sup.-                           60  CH.sub.2 OC.sub.2 H.sub.5                                                               Ph--                                                                              8-(N)-N'-methylpiperazine                                      61  CH.sub.2 OC.sub.2 H.sub.5                                                               Ph--                                                                              8-(N)-N'-dimethylpiperazinium, I.sup.-                         62  CH.sub.2 OC.sub.2 H.sub.5                                                               Ph--                                                                              8-NH-CBZ                                                       63  CH.sub.2 OC.sub.2 H.sub.5                                                               Ph--                                                                              8-NHC(O)C.sub.5 H.sub.11                                       64  CH.sub.2 OC.sub.2 H.sub.5                                                               Ph--                                                                              8-NHC(O)CH.sub.2 Br                                            65  CH.sub.2 OC.sub.2 H.sub.5                                                               Ph--                                                                              8-NH--C(NH)NH.sub.2                                            66  CH.sub.2 OC.sub.2 H.sub.5                                                               Ph--                                                                              8-(2)-thiophene                                                67  CH.sub.2 OC.sub.2 H.sub.5                                                               Ph--                                                                              9-methyl                                                       68  CH.sub.2 OC.sub.2 H.sub.5                                                               Ph--                                                                              9-ethyl                                                        69  CH.sub.2 OC.sub.2 H.sub.5                                                               Ph--                                                                              9-iso-propyl                                                   70  CH.sub.2 OC.sub.2 H.sub.5                                                               Ph--                                                                              9-tert-butyl                                                   71  CH.sub.2 OC.sub.2 H.sub.5                                                               Ph--                                                                              9-OH                                                           72  CH.sub.2 OC.sub.2 H.sub.5                                                               Ph--                                                                              9-OCH.sub.3                                                    73  CH.sub.2 OC.sub.2 H.sub.5                                                               Ph--                                                                              9-O(iso-propyl)                                                74  CH.sub.2 OC.sub.2 H.sub.5                                                               Ph--                                                                              9-SCH.sub.3                                                    75  CH.sub.2 OC.sub.2 H.sub.5                                                               Ph--                                                                              9-SOCH.sub.3                                                   76  CH.sub.2 OC.sub.2 H.sub.5                                                               Ph--                                                                              9-SO.sub.2 CH.sub.3                                            77  CH.sub.2 OC.sub.2 H.sub.5                                                               Ph--                                                                              9-SCH.sub.2 CH.sub.3                                           78  CH.sub.2 OC.sub.2 H.sub.5                                                               Ph--                                                                              9-NH.sub.2                                                     79  CH.sub.2 OC.sub.2 H.sub.5                                                               Ph--                                                                              9-NHOH                                                         80  CH.sub.2 OC.sub.2 H.sub.5                                                               Ph--                                                                              9-NHCH.sub.3                                                   81  CH.sub.2 OC.sub.2 H.sub.5                                                               Ph--                                                                              9-N(CH.sub.3).sub.2                                            82  CH.sub.2 OC.sub.2 H.sub.5                                                               Ph--                                                                              9-N.sup.+ (CH.sub.3).sub.3, I.sup.-                            83  CH.sub.2 OC.sub.2 H.sub.5                                                               Ph--                                                                              9-NHC(═O)CH.sub.3                                          84  CH.sub.2 OC.sub.2 H.sub.5                                                               Ph--                                                                              9-N(CH.sub.2 CH.sub.3).sub.2                                   85  CH.sub.2 OC.sub.2 H.sub.5                                                               Ph--                                                                              9-NMeCH.sub.2 CO.sub.2 H                                       86  CH.sub.2 OC.sub.2 H.sub.5                                                               Ph--                                                                              9-N.sup.+ (Me).sub.2 CH.sub.2 CO.sub.2 H, I.sup.-              87  CH.sub.2 OC.sub.2 H.sub.5                                                               Ph--                                                                              9-(N)-morpholine                                               88  CH.sub.2 OC.sub.2 H.sub.5                                                               Ph--                                                                              9-(N)-azetidine                                                89  CH.sub.2 OC.sub.2 H.sub.5                                                               Ph--                                                                              9-(N)-N-methylazetidinium, I.sup.-                             90  CH.sub.2 OC.sub.2 H.sub.5                                                               Ph--                                                                              9-(N)-pyrrolidine                                              91  CH.sub.2 OC.sub.2 H.sub.5                                                               Ph--                                                                              9-(N)-N-methyl-pyrrolidinium, I.sup.-                          92  CH.sub.2 OC.sub.2 H.sub.5                                                               Ph--                                                                              9-(N)-N-methyl-morpholinium, I.sup.-                           93  CH.sub.2 OC.sub.2 H.sub.5                                                               Ph--                                                                              9-(N)-N'-methylpiperazine                                      93  CH.sub.2 OC.sub.2 H.sub.5                                                               Ph--                                                                              9-(N)-N'-dimethylpiperazinium, I.sup.-                         95  CH.sub.2 OC.sub.2 H.sub.5                                                               Ph--                                                                              9-NH-CBZ                                                       96  CH.sub.2 OC.sub.2 H.sub.5                                                               Ph--                                                                              9-NHC(O)C.sub.5 H.sub.11                                       97  CH.sub.2 OC.sub.2 H.sub.5                                                               Ph--                                                                              9-NHC(O)CH.sub.2 Br                                            98  CH.sub.2 OC.sub.2 H.sub.5                                                               Ph--                                                                              9-NH--C(NH)NH.sub.2                                            99  CH.sub.2 OC.sub.2 H.sub.5                                                               Ph--                                                                              9-(2)-thiophene                                                100 CH.sub.2 OC.sub.2 H.sub.5                                                               Ph--                                                                              7-OCH.sub.3, 8-OCH.sub.3                                       101 CH.sub.2 OC.sub.2 H.sub.5                                                               Ph--                                                                              7-SCH.sub.3, 8-OCH.sub.3                                       102 CH.sub.2 OC.sub.2 H.sub.5                                                               Ph--                                                                              7-SCH.sub.3, 8-SCH.sub.3                                       103 CH.sub.2 OC.sub.2 H.sub.5                                                               Ph--                                                                              6-OCH.sub.3, 7-OCH.sub.3, 8-OCH.sub.3                   F101.011                                                                              01  CH.sub.2 CH(OH)C.sub.2 H.sub.5                                                          Ph--                                                                              7-methyl                                                       02  CH.sub.2 CH(OH)C.sub.2 H.sub.5                                                          Ph--                                                                              7-ethyl                                                        03  CH.sub.2 CH(OH)C.sub.2 H.sub.5                                                          Ph--                                                                              7-iso-propyl                                                   04  CH.sub.2 CH(OH)C.sub.2 H.sub.5                                                          Ph--                                                                              7-tert-butyl                                                   05  CH.sub.2 CH(OH)C.sub.2 H.sub.5                                                          Ph--                                                                              7-OH                                                           06  CH.sub.2 CH(OH)C.sub.2 H.sub.5                                                          Ph--                                                                              7-OCH.sub.3                                                    07  CH.sub.2 CH(OH)C.sub.2 H.sub.5                                                          Ph--                                                                              7-O(iso-propyl)                                                08  CH.sub.2 CH(OH)C.sub.2 H.sub.5                                                          Ph--                                                                              7-SCH.sub.3                                                    09  CH.sub.2 CH(OH)C.sub.2 H.sub.5                                                          Ph--                                                                              7-SOCH.sub.3                                                   10  CH.sub.2 CH(OH)C.sub.2 H.sub.5                                                          Ph--                                                                              7-SO.sub.2 CH.sub.3                                            11  CH.sub.2 CH(OH)C.sub.2 H.sub.5                                                          Ph--                                                                              7-SCH.sub.2 CH.sub.3                                           12  CH.sub.2 CH(OH)C.sub.2 H.sub.5                                                          Ph--                                                                              7-NH.sub.2                                                     13  CH.sub.2 CH(OH)C.sub.2 H.sub.5                                                          Ph--                                                                              7-NHOH                                                         14  CH.sub.2 CH(OH)C.sub.2 H.sub.5                                                          Ph--                                                                              7-NHCH.sub.3                                                   15  CH.sub.2 CH(OH)C.sub.2 H.sub.5                                                          Ph--                                                                              7-N(CH.sub.3).sub.2                                            16  CH.sub.2 CH(OH)C.sub.2 H.sub.5                                                          Ph--                                                                              7-N.sup.+ (CH.sub.3).sub.3, I.sup.-                            17  CH.sub.2 CH(OH)C.sub.2 H.sub.5                                                          Ph--                                                                              7-NHC(═O)CH.sub.3                                          18  CH.sub.2 CH(OH)C.sub.2 H.sub.5                                                          Ph--                                                                              7-N(CH.sub.2 CH.sub.3).sub.2                                   19  CH.sub.2 CH(OH)C.sub.2 H.sub.5                                                          Ph--                                                                              7-NMeCH.sub.2 CO.sub.2 H                                       20  CH.sub.2 CH(OH)C.sub.2 H.sub.5                                                          Ph--                                                                              7-N.sup.+ (Me).sub.2 CH.sub.2 CO.sub.2 H, I.sup.-              21  CH.sub.2 CH(OH)C.sub.2 H.sub.5                                                          Ph--                                                                              7-(N)-morpholine                                               22  CH.sub.2 CH(OH)C.sub.2 H.sub.5                                                          Ph--                                                                              7-(N)-azetidine                                                23  CH.sub.2 CH(OH)C.sub.2 H.sub.5                                                          Ph--                                                                              7-(N)-N-methylazetidinium, I.sup.-                             24  CH.sub.2 CH(OH)C.sub.2 H.sub.5                                                          Ph--                                                                              7-(N)-pyrrolidine                                              25  CH.sub.2 CH(OH)C.sub.2 H.sub.5                                                          Ph--                                                                              7-(N)-N-methyl-pyrrolidinium, I.sup.-                          26  CH.sub.2 CH(OH)C.sub.2 H.sub.5                                                          Ph--                                                                              7-(N)-N-methyl-morpholinium, I.sup.-                           27  CH.sub.2 CH(OH)C.sub.2 H.sub.5                                                          Ph--                                                                              7-(N)-N'-methylpiperazine                                      28  CH.sub.2 CH(OH)C.sub.2 H.sub.5                                                          Ph--                                                                              7-(N)-N'-dimethylpiperazinium, I.sup.-                         29  CH.sub.2 CH(OH)C.sub.2 H.sub.5                                                          Ph--                                                                              7-NH-CBZ                                                       30  CH.sub.2 CH(OH)C.sub.2 H.sub.5                                                          Ph--                                                                              7-NHC(O)C.sub.5 H.sub.11                                       31  CH.sub.2 CH(OH)C.sub.2 H.sub.5                                                          Ph--                                                                              7-NHC(O)CH.sub.2 Br                                            32  CH.sub.2 CH(OH)C.sub.2 H.sub.5                                                          Ph--                                                                              7-NH--C(NH)NH.sub.2                                            33  CH.sub.2 CH(OH)C.sub.2 H.sub.5                                                          Ph--                                                                              7-(2)-thiophene                                                34  CH.sub.2 CH(OH)C.sub.2 H.sub.5                                                          Ph--                                                                              8-methyl                                                       35  CH.sub.2 CH(OH)C.sub.2 H.sub.5                                                          Ph--                                                                              8-ethyl                                                        36  CH.sub.2 CH(OH)C.sub.2 H.sub.5                                                          Ph--                                                                              8-iso-propyl                                                   37  CH.sub.2 CH(OH)C.sub.2 H.sub.5                                                          Ph--                                                                              8-tert-butyl                                                   38  CH.sub.2 CH(OH)C.sub.2 H.sub.5                                                          Ph--                                                                              8-OH                                                           39  CH.sub.2 CH(OH)C.sub.2 H.sub.5                                                          Ph--                                                                              8-OCH.sub.3                                                    40  CH.sub.2 CH(OH)C.sub.2 H.sub.5                                                          Ph--                                                                              8-O(iso-propyl)                                                41  CH.sub.2 CH(OH)C.sub.2 H.sub.5                                                          Ph--                                                                              8-SCH.sub.3                                                    42  CH.sub.2 CH(OH)C.sub.2 H.sub.5                                                          Ph--                                                                              8-SOCH.sub.3                                                   43  CH.sub.2 CH(OH)C.sub.2 H.sub.5                                                          Ph--                                                                              8-SO.sub.2 CH.sub.3                                            44  CH.sub.2 CH(OH)C.sub.2 H.sub.5                                                          Ph--                                                                              8-SCH.sub.2 CH.sub.3                                           45  CH.sub.2 CH(OH)C.sub.2 H.sub.5                                                          Ph--                                                                              8-NH.sub.2                                                     46  CH.sub.2 CH(OH)C.sub.2 H.sub.5                                                          Ph--                                                                              8-NHOH                                                         47  CH.sub.2 CH(OH)C.sub.2 H.sub.5                                                          Ph--                                                                              8-NHCH.sub.3                                                   48  CH.sub.2 CH(OH)C.sub.2 H.sub.5                                                          Ph--                                                                              8-N(CH.sub.3).sub.2                                            49  CH.sub.2 CH(OH)C.sub.2 H.sub.5                                                          Ph--                                                                              8-N.sup.+ (CH.sub.3).sub.3, I.sup.-                            50  CH.sub.2 CH(OH)C.sub.2 H.sub.5                                                          Ph--                                                                              8-NHC(═O)CH.sub.3                                          51  CH.sub.2 CH(OH)C.sub.2 H.sub.5                                                          Ph--                                                                              8-N(CH.sub.2 CH.sub.3).sub.2                                   52  CH.sub.2 CH(OH)C.sub.2 H.sub.5                                                          Ph--                                                                              8-NMeCH.sub.2 CO.sub.2 H                                       53  CH.sub.2 CH(OH)C.sub.2 H.sub.5                                                          Ph--                                                                              8-N.sup.+ (Me).sub.2 CH.sub.2 CO.sub.2 H, I.sup.-              54  CH.sub.2 CH(OH)C.sub.2 H.sub.5                                                          Ph--                                                                              8-(N)-morpholine                                               55  CH.sub.2 CH(OH)C.sub.2 H.sub.5                                                          Ph--                                                                              8-(N)-azetidine                                                56  CH.sub.2 CH(OH)C.sub.2 H.sub.5                                                          Ph--                                                                              8-(N)-N-methylazetidinium, I.sup.-                             57  CH.sub.2 CH(OH)C.sub.2 H.sub.5                                                          Ph--                                                                              8-(N)-pyrrolidine                                              58  CH.sub.2 CH(OH)C.sub.2 H.sub.5                                                          Ph--                                                                              8-(N)-N-methyl-pyrrolidinium1 I.sup.-                          59  CH.sub.2 CH(OH)C.sub.2 H.sub.5                                                          Ph--                                                                              8-(N)-N-methyl-morpholinium, I.sup.-                           60  CH.sub.2 CH(OH)C.sub.2 H.sub.5                                                          Ph--                                                                              8-(N)-N'-methylpiperazine                                      61  CH.sub.2 CH(OH)C.sub.2 H.sub.5                                                          Ph--                                                                              8-(N)-N'-dimethylpiperazinium, I.sup.-                         62  CH.sub.2 CH(OH)C.sub.2 H.sub.5                                                          Ph--                                                                              8-NH-CBZ                                                       63  CH.sub.2 CH(OH)C.sub.2 H.sub.5                                                          Ph--                                                                              8-NHC(0)C.sub.5 H.sub.11                                       64  CH.sub.2 CH(OH)C.sub.2 H.sub.5                                                          Ph--                                                                              8-NHC(O)CH.sub.2 Br                                            65  CH.sub.2 CH(OH)C.sub.2 H.sub.5                                                          Ph--                                                                              8-NH--C(NH)NH.sub.2                                            66  CH.sub.2 CH(OH)C.sub.2 H.sub.5                                                          Ph--                                                                              8-(2)-thiophene                                                67  CH.sub.2 CH(OH)C.sub.2 H.sub.5                                                          Ph--                                                                              9-methyl                                                       68  CH.sub.2 CH(OH)C.sub.2 H.sub.5                                                          Ph--                                                                              9-ethyl                                                        69  CH.sub.2 CH(OH)C.sub.2 H.sub.5                                                          Ph--                                                                              9-iso-propyl                                                   70  CH.sub.2 CH(OH)C.sub.2 H.sub.5                                                          Ph--                                                                              9-tert-butyl                                                   71  CH.sub.2 CH(OH)C.sub.2 H.sub.5                                                          Ph--                                                                              9-OH                                                           72  CH.sub.2 CH(OH)C.sub.2 H.sub.5                                                          Ph--                                                                              9-OCH.sub.3                                                    73  CH.sub.2 CH(OH)C.sub.2 H.sub.5                                                          Ph--                                                                              9-O(iso-propyl)                                                74  CH.sub.2 CH(OH)C.sub.2 H.sub.5                                                          Ph--                                                                              9-SCH.sub.3                                                    75  9H2CH(OH)C.sub.2 H.sub.5                                                                Ph--                                                                              9-SOCH.sub.3                                                   76  CH.sub.2 CH(OH)C.sub.2 H.sub.5                                                          Ph--                                                                              9-SO.sub.2 CH.sub.3                                            77  CH.sub.2 CH(OH)C.sub.2 H.sub.5                                                          Ph--                                                                              9-SCH.sub.2 CH.sub.3                                           78  CH.sub.2 CH(OH)C.sub.2 H.sub.5                                                          Ph--                                                                              9-NH.sub.2                                                     79  CH.sub.2 CH(OH)C.sub.2 H.sub.5                                                          Ph--                                                                              9-NHOH                                                         80  CH.sub.2 CH(OH)C.sub.2 H.sub.5                                                          Ph--                                                                              9-NHCH.sub.3                                                   81  CH.sub.2 CH(OH)C.sub.2 H.sub.5                                                          Ph--                                                                              9-N(CH.sub.3).sub.2                                            82  CH.sub.2 CH(OH)C.sub.2 H.sub.5                                                          Ph--                                                                              9-N.sup.+ (CH.sub.3).sub.3, I.sup.-                            83  CH.sub.2 CH(OH)C.sub.2 H.sub.5                                                          Ph--                                                                              9-NHC(═O)CH.sub.3                                          84  CH.sub.2 CH(OH)C.sub.2 H.sub.5                                                          Ph--                                                                              9-N(CH.sub.2 CH.sub.3).sub.2                                   85  CH.sub.2 CH(OH)C.sub.2 H.sub.5                                                          Ph--                                                                              9-NMeCH.sub.2 CO.sub.2 H                                       86  CH.sub.2 CH(OH)C.sub.2 H.sub.5                                                          Ph--                                                                              9-N.sup.+ (Me).sub.2 CH.sub.2 CO.sub.2 H, I.sup.-              87  CH.sub.2 CH(OH)C.sub.2 H.sub.5                                                          Ph--                                                                              9-(N)-morpholine                                               88  CH.sub.2 CH(OH)C.sub.2 H.sub.5                                                          Ph--                                                                              9-(N)-azetidine                                                89  CH.sub.2 CH(OH)C.sub.2 H.sub.5                                                          Ph--                                                                              9-(N)-N-methylazetidinium, I.sup.-                             90  CH.sub.2 CH(OH)C.sub.2 H.sub.5                                                          Ph--                                                                              9-(N)-pyrrolidine                                              91  CH.sub.2 CH(OH)C.sub.2 H.sub.5                                                          Ph--                                                                              9-(N)-N-methyl-pyrrolidinium, I.sup.-                          92  CH.sub.2 CH(OH)C.sub.2 H.sub.5                                                          Ph--                                                                              9-(N)-N-methyl-morpholinium, I.sup.-                           93  CH.sub.2 CH(OH)C.sub.2 H.sub.5                                                          Ph--                                                                              9-(N)-N'-methylpiperazine                                      93  CH.sub.2 CH(OH)C.sub.2 H.sub.5                                                          Ph--                                                                              9-(N)-N'-dimethylpiperazinium, I.sup.-                         95  CH.sub.2 CH(OH)C.sub.2 H.sub.5                                                          Ph--                                                                              9-NH-CBZ                                                       96  CH.sub.2 CH(OH)C.sub.2 H.sub.5                                                          Ph--                                                                              9-NHC(O)C.sub.5 H.sub.11                                       97  CH.sub.2 CH(OH)C.sub.2 H.sub.5                                                          Ph--                                                                              9-NHC(O)CH.sub.2 Br                                            98  CH.sub.2 CH(OH)C.sub.2 H.sub.5                                                          Ph--                                                                              9-NH--C(NH)NH.sub.2                                            99  CH.sub.2 CH(OH)C.sub.2 H.sub.5                                                          Ph--                                                                              9-(2)-thiophene                                                100 CH.sub.2 CH(OH)C.sub.2 H.sub.5                                                          Ph--                                                                              7-OCH.sub.3, 8-OCH.sub.3                                       101 CH.sub.2 CH(OH)C.sub.2 H.sub.5                                                          Ph--                                                                              7-SCH.sub.3, 8-OCH.sub.3                                       102 CH.sub.2 CH(OH)C.sub.2 H.sub.5                                                          Ph--                                                                              7-SCH.sub.3, 8-SCH.sub.3                                       103 CH.sub.2 CH(OH)C.sub.2 H.sub.5                                                          Ph--                                                                              6-OCH.sub.3, 7-OCH.sub.3, 8-OCH.sub.3                   F101.012                                                                              01  CH.sub.2 O-(4-picoline)                                                                 Ph--                                                                              7-methyl                                                       02  CH.sub.2 O-(4-picoline)                                                                 Ph--                                                                              7-ethyl                                                        03  CH.sub.2 O-(4-picoline)                                                                 Ph--                                                                              7-iso-propyl                                                   04  CH.sub.2 O-(4-picoline)                                                                 Ph--                                                                              7-tert-butyl                                                   05  CH.sub.2 O-(4-picoline)                                                                 Ph--                                                                              7-OH                                                           06  CH.sub.2 O-(4-picoline)                                                                 Ph--                                                                              7-OCH.sub.3                                                    07  CH.sub.2 O-(4-picoline)                                                                 Ph--                                                                              7-O(iso-propyl)                                                08  CH.sub.2 O-(4-picoline)                                                                 Ph--                                                                              7-SCH.sub.3                                                    09  CH.sub.2 O-(4-picoline)                                                                 Ph--                                                                              7-SOCH.sub.3                                                   10  CH.sub.2 O-(4-picoline)                                                                 Ph--                                                                              7-SO.sub.2 CH.sub.3                                            11  CH.sub.2 O-(4-picoline)                                                                 Ph--                                                                              7-SCH.sub.2 CH.sub.3                                           12  CH.sub.2 O-(4-picoline)                                                                 Ph--                                                                              7-NH.sub.2                                                     13  CH.sub.2 O-(4-picoline)                                                                 Ph--                                                                              7-NHOH                                                         14  CH.sub.2 O-(4-picoline)                                                                 Ph--                                                                              7-NHCH.sub.3                                                   15  CH.sub.2 O-(4-picoline)                                                                 Ph--                                                                              7-N(CH.sub.3).sub.2                                            16  CH.sub.2 O-(4-picoline)                                                                 Ph--                                                                              7-N.sup.+ (CH.sub.3).sub.3, I.sup.-                            17  CH.sub.2 O-(4-picoline)                                                                 Ph--                                                                              7-NHC(═O)CH.sub.3                                          18  CH.sub.2 O-(4-picoline)                                                                 Ph--                                                                              7-N(CH.sub.2 CH.sub.3).sub.2                                   19  CH.sub.2 O-(4-picoline)                                                                 Ph--                                                                              7-NMeCH.sub.2 CO.sub.2 H                                       20  CH.sub.2 O-(4-picoline)                                                                 Ph--                                                                              7-N.sup.+ (Me).sub.2 CH.sub.2 CO.sub.2 H, I.sup.-              21  CH.sub.2 O-(4-picoline)                                                                 Ph--                                                                              7-(N)-morpholine                                               22  CH.sub.2 O-(4-picoline)                                                                 Ph--                                                                              7-(N)-azetidine                                                23  CH.sub.2 O-(4-picoline)                                                                 Ph--                                                                              7-(N)-N-methylazetidinium, I.sup.-                             24  CH.sub.2 O-(4-picoline)                                                                 Ph--                                                                              7-(N)-pyrrolidine                                              25  CH.sub.2 O-(4-picoline)                                                                 Ph--                                                                              7-(N)-N-methyl-pyrrolidinium, I.sup.-                          26  CH.sub.2 O-(4-picoline)                                                                 Ph--                                                                              7-(N)-N-methyl-morpholinium, I.sup.-                           27  CH.sub.2 O-(4-picoline)                                                                 Ph--                                                                              7-(N)-N'-methylpiperazine                                      28  CH.sub.2 O-(4-picoline)                                                                 Ph--                                                                              7-(N)-N'-dimethylpiperazinium, I.sup.-                         29  CH.sub.2 O-(4-picoline)                                                                 Ph--                                                                              7-NH-CBZ                                                       30  CH.sub.2 O-(4-picoline)                                                                 Ph--                                                                              7-NHC(O)C.sub.5 H.sub.11                                       31  CH.sub.2 O-(4-picoline)                                                                 Ph--                                                                              7-NHC(O)CH.sub.2 Br                                            32  CH.sub.2 O-(4-picoline)                                                                 Ph--                                                                              7-NH--C(NH)NH.sub.2                                            33  CH.sub.2 O-(4-picoline)                                                                 Ph--                                                                              7-(2)-thiophene                                                34  CH.sub.2 O-(4-picoline)                                                                 Ph--                                                                              8-methyl                                                       35  CH.sub.2 O-(4-picoline)                                                                 Ph--                                                                              8-ethyl                                                        36  CH.sub.2 O-(4-picoline)                                                                 Ph--                                                                              8-iso-propyl                                                   37  CH.sub.2 O-(4-picoline)                                                                 Ph--                                                                              8-tert-butyl                                                   38  CH.sub.2 O-(4-picoline)                                                                 Ph--                                                                              8-OH                                                           39  CH.sub.2 O-(4-picoline)                                                                 Ph--                                                                              8-OCH.sub.3                                                    40  CH.sub.2 O-(4-picoline)                                                                 Ph--                                                                              8-O(iso-propyl)                                                41  CH.sub.2 O-(4-picoline)                                                                 Ph--                                                                              8-SCH.sub.3                                                    42  CH.sub.2 O-(4-picoline)                                                                 Ph--                                                                              8-SOCH.sub.3                                                   43  CH.sub.2 O-(4-picoline)                                                                 Ph--                                                                              8-SO.sub.2 CH.sub.3                                            44  CH.sub.2 O-(4-picoline)                                                                 Ph--                                                                              8-SCH.sub.2 CH.sub.3                                           45  CH.sub.2 O-(4-picoline)                                                                 Ph--                                                                              8-NH.sub.2                                                     46  CH.sub.2 O-(4-picoline)                                                                 Ph--                                                                              8-NHOH                                                         47  CH.sub.2 O-(4-picoline)                                                                 Ph--                                                                              8-NHCH.sub.3                                                   48  CH.sub.2 O-(4-picoline)                                                                 Ph--                                                                              8-N(CH.sub.3).sub.2                                            49  CH.sub.2 O-(4-picoline)                                                                 Ph--                                                                              8-N.sup.+ (CH.sub.3).sub.3, I.sup.-                            50  CH.sub.2 O-(4-picoline)                                                                 Ph--                                                                              8-NHC(═O)CH.sub.3                                          51  CH.sub.2 O-(4-picoline)                                                                 Ph--                                                                              8-N(CH.sub.2 CH.sub.3).sub.2                                   52  CH.sub.2 O-(4-picoline)                                                                 Ph--                                                                              8-NMeCH.sub.2 CO.sub.2 H                                       53  CH.sub.2 O-(4-picoline)                                                                 Ph--                                                                              8-N.sup.+ (Me).sub.2 CH.sub.2 CO.sub.2 H, I.sup.-              54  CH.sub.2 O-(4-picoline)                                                                 Ph--                                                                              8-(N)-morpholine                                               55  CH.sub.2 O-(4-picoline)                                                                 Ph--                                                                              8-(N)-azetidine                                                56  CH.sub.2 O-(4-picoline)                                                                 Ph--                                                                              8-(N)-N-methylazetidinium, I.sup.-                             57  CH.sub.2 O-(4-picoline)                                                                 Ph--                                                                              8-(N)-pyrrolidine                                              58  CH.sub.2 O-(4-picoline)                                                                 Ph--                                                                              8-(N)-N-methyl-pyrrolidinium, I.sup.-                          59  CH.sub.2 O-(4-picoline)                                                                 Ph--                                                                              8-(N)-N-methyl-morpholinium, I.sup.-                           60  CH.sub.2 O-(4-picoline)                                                                 Ph--                                                                              8-(N)-N'-methylpiperazine                                      61  CH.sub.2 O-(4-picoline)                                                                 Ph--                                                                              8-(N)-N'-dimethylpiperazinium, I.sup.-                         62  CH.sub.2 O-(4-picoline)                                                                 Ph--                                                                              8-NH-CBZ                                                       63  CH.sub.2 O-(4-picoline)                                                                 Ph--                                                                              8-NHC(O)C.sub.5 H.sub.11                                       64  CH.sub.2 O-(4-picoline)                                                                 Ph--                                                                              8-NHC(O)CH.sub.2 Br                                            65  CH.sub.2 O-(4-picoline)                                                                 Ph--                                                                              8-NH--C(NH)NH.sub.2                                            66  CH.sub.2 O-(4-picoline)                                                                 Ph--                                                                              8-(2)-thiophene                                                67  CH.sub.2 O-(4-picoline)                                                                 Ph--                                                                              9-methyl                                                       68  CH.sub.2 O-(4-picoline)                                                                 Ph--                                                                              9-ethyl                                                        69  CH.sub.2 O-(4-picoline)                                                                 Ph--                                                                              9-iso-propyl                                                   70  CH.sub.2 O-(4-picoline)                                                                 Ph--                                                                              9-tert-butyl                                                   71  CH.sub.2 O-(4-picoline)                                                                 Ph--                                                                              9-OH                                                           72  CH.sub.2 O-(4-picoline)                                                                 Ph--                                                                              9-OCH.sub.3                                                    73  CH.sub.2 O-(4-picoline)                                                                 Ph--                                                                              9-O(iso-propyl)                                                74  CH.sub.2 O-(4-picoline)                                                                 Ph--                                                                              9-SCH.sub.3                                                    75  CH.sub.2 O-(4-picoline)                                                                 Ph--                                                                              9-SOCH.sub.3                                                   76  CH.sub.2 O-(4-picoline)                                                                 Ph--                                                                              9-SO.sub.2 CH.sub.3                                            77  CH.sub.2 O-(4-picoline)                                                                 Ph--                                                                              9-SCH.sub.2 CH.sub.3                                           78  CH.sub.2 O-(4-picoline)                                                                 Ph--                                                                              9-NH.sub.2                                                     79  CH.sub.2 O-(4-picoline)                                                                 Ph--                                                                              9-NHOH                                                         80  CH.sub.2 O-(4-picoline)                                                                 Ph--                                                                              9-NHCH.sub.3                                                   81  CH.sub.2 O-(4-picoline)                                                                 Ph--                                                                              9-N(CH.sub.3).sub.2                                            82  CH.sub.2 O-(4-picoline)                                                                 Ph--                                                                              9-N.sup.+ (CH.sub.3).sub.3, I.sup.-                            83  CH.sub.2 O-(4-picoline)                                                                 Ph--                                                                              9-NHC(═O)CH.sub.3                                          84  CH.sub.2 O-(4-picoline)                                                                 Ph--                                                                              9-N(CH.sub.2 CH.sub.3).sub.2                                   85  CH.sub.2 O-(4-picoline)                                                                 Ph--                                                                              9-NMeCH.sub.2 CO.sub.2 H                                       86  CH.sub.2 O-(4-picoline)                                                                 Ph--                                                                              9-N.sup.+ (Me).sub.2 CH.sub.2 CO.sub.2 H, I.sup.-              87  CH.sub.2 O-(4-picoline)                                                                 Ph--                                                                              9-(N)-morpholine                                               88  CH.sub.2 O-(4-picoline)                                                                 Ph--                                                                              9-(N)-azetidine                                                89  CH.sub.2 O-(4-picoline)                                                                 Ph--                                                                              9-(N)-N-methylazetidinium, I.sup.-                             90  CH.sub.2 O-(4-picoline)                                                                 Ph--                                                                              9-(N)-pyrrolidine                                              91  CH.sub.2 O-(4-picoline)                                                                 Ph--                                                                              9-(N)-N-methyl-pyrrolidinium, I.sup.-                          92  CH.sub.2 O-(4-picoline)                                                                 Ph--                                                                              9-(N)-N-methyl-morpholinium, I.sup.-                           93  CH.sub.2 O-(4-picoline)                                                                 Ph--                                                                              9-(N)-N'-methylpiperazine                                      93  CH.sub.2 O-(4-picoline)                                                                 Ph--                                                                              9-(N)-N'-dimethylpiperazinium, I.sup.-                         95  CH.sub.2 O-(4-picoline)                                                                 Ph--                                                                              9-NH-CBZ                                                       96  CH.sub.2 O-(4-picoline)                                                                 Ph--                                                                              9-NHC(O)C.sub.5 H.sub.11                                       97  CH.sub.2 O-(4-picoline)                                                                 Ph--                                                                              9-NHC(O)CH.sub.2 Br                                            98  CH.sub.2 O-(4-picoline)                                                                 Ph--                                                                              9-NH--C(NH)NH.sub.2                                            99  CH.sub.2 O-(4-picoline)                                                                 Ph--                                                                              9-(2)-thiophene                                                100 CH.sub.2 O-(4-picoline)                                                                 Ph--                                                                              7-OCH.sub.3, 8-OCH.sub.3                                       101 CH.sub.2 O-(4-picoline)                                                                 Ph--                                                                              7-SCH.sub.3, 8-OCH.sub.3                                       102 CH.sub.2 O-(4-picoline)                                                                 Ph--                                                                              7-SCH.sub.3, 8-SCH.sub.3                                       103 CH.sub.2 O-(4-picoline)                                                                 Ph--                                                                              6-OCH.sub.3, 7-OCH.sub.3, 8-OCH.sub.3                   __________________________________________________________________________

    __________________________________________________________________________     Additional Structures of the Present Invention                                  ##STR18##                                                                     __________________________________________________________________________     Compound                                                                       Number                                                                               R.sup.1                                                                            R.sup.2                                                                            R.sup.3                                                                            R.sup.4                                                                           R.sup.5                                                   __________________________________________________________________________      101  ethyl                                                                              n-butyl                                                                            OH  H  phenyl                                                     102  ethyl                                                                              n-butyl                                                                            OH  H  phenyl                                                     103  n-butyl                                                                            ethyl                                                                              OH  H  phenyl                                                     104  ethyl                                                                              n-butyl                                                                            OH  H  phenyl                                                     105  ethyl                                                                              n-butyl                                                                            OH  H  phenyl                                                     106  ethyl                                                                              n-butyl                                                                            OH  H  phenyl                                                     107  n-butyl                                                                            ethyl                                                                              OH  H  4-(decyloxy)phenyl                                         108  ethyl                                                                              n-butyl                                                                            OH  H  phenyl                                                     109  ethyl                                                                              n-butyl                                                                            OH  H  4-(decyloxy)phenyl                                         110  ethyl                                                                              n-butyl                                                                            OH  H  phenyl                                                     111  n-butyl                                                                            ethyl                                                                              OH  H  4-hydroxyphenyl                                            112  ethyl                                                                              n-butyl                                                                            OH  H                                                                                  ##STR19##                                                 113  ethyl                                                                              n-butyl                                                                            OH  H  4-hydroxyphenyl                                            114  ethyl                                                                              n-butyl                                                                            OH  H  4-methoxyphenyl                                            115  n-butyl                                                                            ethyl                                                                              OH  H  4-methoxyphenyl                                            116  ethyl                                                                              n-butyl                                                                            OH  H  4-methoxyphenyl                                            117  n-butyl                                                                            ethyl                                                                              OH  H  phenyl                                                     118  ethyl                                                                              n-butyl                                                                            OH  H  phenyl                                                     119  ethyl                                                                              n-butyl                                                                            OH  H  phenyl                                                     120  n-butyl                                                                            ethyl                                                                              OH  H  phenyl                                                     121  ethyl                                                                              n-butyl                                                                            OH  H  phenyl                                                     122  n-butyl                                                                            ethyl                                                                              OH  H  phenyl                                                     123  ethyl                                                                              n-butyl                                                                            OH  H  phenyl                                                     124  n-butyl                                                                            ethyl                                                                              OH  H  phenyl                                                     125  ethyl                                                                              n-butyl                                                                            OH  H  phenyl                                                     126  n-butyl                                                                            ethyl                                                                              OH  H  4-fluorophenyl                                             127  n-butyl                                                                            ethyl                                                                              OH  H  4-fluorophenyl                                             128  ethyl                                                                              n-butyl                                                                            OH  H  4-fluorophenyl                                             129  ethyl                                                                              n-butyl                                                                            OH  H  4-fluorophenyl                                             131  ethyl                                                                              n-butyl                                                                            OH  H  4-fluorophenyl                                             132  ethyl                                                                              n-butyl                                                                            OH  H  phenyl                                                     133  ethyl                                                                              n-butyl                                                                            OH  H  phenyl                                                     134  ethyl                                                                              n-butyl                                                                            OH  H  phenyl                                                     135  ethyl                                                                              n-butyl                                                                            OH  H  phenyl                                                     136  ethyl                                                                              n-butyl                                                                            OH  H  phenyl                                                     137  n-butyl                                                                            ethyl                                                                              OH  H  phenyl                                                     138  n-butyl                                                                            ethyl                                                                              OH  H  phenyl                                                     139  n-butyl                                                                            ethyl                                                                              OH  H  phenyl                                                     140                                                                            141                                                                            142  ethyl                                                                              n-butyl                                                                            H   OH H                                                          143  ethyl                                                                              n-butyl                                                                            OH  H  3-methoxyphenyl                                            144  ethyl                                                                              n-butyl                                                                            OH  H  4-fluorophenyl                                             262  ethyl                                                                              n-butyl                                                                            OH  H  3-methoxyphenyl                                            263  ethyl                                                                              n-butyl                                                                            H   OH H                                                          264  ethyl                                                                              n-butyl                                                                            OH  H  3-trifluoromethylphenyl                                    265  ethyl                                                                              n-butyl                                                                            H   OH H                                                          266  ethyl                                                                              n-butyl                                                                            OH  H  3-hydroxyphenyl                                            267  ethyl                                                                              n-butyl                                                                            OH  H  3-hydroxyphenyl                                            268  ethyl                                                                              n-butyl                                                                            OH  H  4-fluorophenyl                                             269  ethyl                                                                              n-butyl                                                                            H   OH H                                                          270  ethyl                                                                              n-butyl                                                                            OH  H  4-fluorophenyl                                             271  ethyl                                                                              n-butyl                                                                            OH  H  3-methoxyphenyl                                            272  ethyl                                                                              n-butyl                                                                            H   OH H                                                          273  ethyl                                                                              n-butyl                                                                            H   OH H                                                          274  ethyl                                                                              n-butyl                                                                            OH  H  4-fluorophenyl                                             275  ethyl                                                                              n-butyl                                                                            H   OH H                                                          276  ethyl                                                                              n-butyl                                                                            OH  H  3-methoxyphenyl                                            277  ethyl                                                                              n-butyl                                                                            OH  H  3-fluorophenyl                                             278  ethyl                                                                              n-butyl                                                                            H   OH 2-fluorophenyl                                             279  ethyl                                                                              n-butyl                                                                            H   OH 3-fluorophenyl                                             280  ethyl                                                                              n-butyl                                                                            OH  H  2-fluorophenyl                                             281  ethyl                                                                              n-butyl                                                                            OH  H  4-fluorophenyl                                             282  ethyl                                                                              n-butyl                                                                            OH  H  4-fluorophenyl                                             283  ethyl                                                                              n-butyl                                                                            H   OH H                                                          284  ethyl                                                                              n-butyl                                                                            OH  H  4-fluorophenyl                                             286  ethyl                                                                              ethyl                                                                              OH  H  phenyl                                                     287  ethyl                                                                              ethyl                                                                              OH  H  phenyl                                                     288  methyl                                                                             methyl                                                                             OH  H  phenyl                                                     289  n-butyl                                                                            n-butyl                                                                            OH  H  phenyl                                                     290  n-butyl                                                                            n-butyl                                                                            OH  H  phenyl                                                     291  n-butyl                                                                            n-butyl                                                                            OH  H  phenyl                                                     292  n-butyl                                                                            n-butyl                                                                            OH  H  4-fluorophenyl                                             293  n-butyl                                                                            n-butyl                                                                            OH  H  phenyl                                                     294  n-butyl                                                                            n-butyl                                                                            OH  H  phenyl                                                     295  ethyl                                                                              n-butyl                                                                            OH  H                                                                                  ##STR20##                                                 296  ethyl                                                                              n-butyl                                                                            OH  H                                                                                  ##STR21##                                                1000  ethyl                                                                              n-butyl                                                                            OH  H                                                                                  ##STR22##                                                1001  ethyl                                                                              n-butyl                                                                            OH  H                                                                                  ##STR23##                                                1002  ethyl                                                                              n-butyl                                                                            OH  H                                                                                  ##STR24##                                                1003  ethyl                                                                              n-butyl                                                                            OH  H                                                                                  ##STR25##                                                1004  ethyl                                                                              n-butyl                                                                            OH  H                                                                                  ##STR26##                                                1005  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR27##                                                1006  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR28##                                                1007  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR29##                                                1008  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR30##                                                1009  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR31##                                                1010  n-butyl                                                                            n-butyl                                                                            OH  H  3-fluoro-4-methoxyphenyl                                  1011  n-butyl                                                                            n-butyl                                                                            OH  H  3-fluoro-4-(5-triethylammoniumpentyloxy)phenyl,                                trifluoroacetate salt                                     1012  n-butyl                                                                            n-butyl                                                                            OH  H  4-hydroxyphenyl                                           1013  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR32##                                                1014  n-butyl                                                                            n-butyl                                                                            OH  H  4-methoxyphenyl                                           1015  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR33##                                                1016  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR34##                                                1017  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR35##                                                1018  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR36##                                                1019  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR37##                                                1020  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR38##                                                1021  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR39##                                                1022  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR40##                                                1023  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR41##                                                1024  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR42##                                                1025  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR43##                                                1026  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR44##                                                1027  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR45##                                                1028  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR46##                                                1029  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR47##                                                1030  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR48##                                                1031  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR49##                                                1032  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR50##                                                1033  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR51##                                                1034  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR52##                                                1035  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR53##                                                1036  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR54##                                                1037  n-butyl                                                                            n-butyl                                                                            OH  H  4-hydroxyphenyl                                           1038  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR55##                                                1039  n-butyl                                                                            n-butyl                                                                            OH  H  phenyl                                                    1040  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR56##                                                1041  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR57##                                                1042  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR58##                                                1043  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR59##                                                1044  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR60##                                                1045  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR61##                                                1046  n-butyl                                                                            n-butyl                                                                            OH  H  3-aminophenyl                                             1047  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR62##                                                1048  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR63##                                                1049  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR64##                                                1050  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR65##                                                1051  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR66##                                                1052  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR67##                                                1053  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR68##                                                1054  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR69##                                                1055  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR70##                                                1056  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR71##                                                1057  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR72##                                                1058  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR73##                                                1059  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR74##                                                1060  ethyl                                                                              n-butyl                                                                            OH  H  3-fluoro-4-methoxyphenyl                                  1061  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR75##                                                1062  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR76##                                                1063  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR77##                                                1064  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR78##                                                1065  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR79##                                                1066  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR80##                                                1067  n-butyl                                                                            n-butyl                                                                            OH  H  thiophen-3-yl                                             1068  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR81##                                                1069  n-butyl                                                                            n-butyl                                                                            OH  H  phenyl                                                    1070  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR82##                                                1071  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR83##                                                1072  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR84##                                                1073  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR85##                                                1074  ethyl                                                                              n-butyl                                                                            OH  H  3-fluoro-4-methoxyphenyl                                  1075  n-butyl                                                                            n-butyl                                                                            OH  H  4-fluorophenyl                                            1076  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR86##                                                1077  n-butyl                                                                            n-butyl                                                                            OH  H  3-hydroxymethylphenyl                                     1078  ethyl                                                                              n-butyl                                                                            OH  H  4-hydroxyphenyl                                           1079  ethyl                                                                              n-butyl                                                                            OH  H                                                                                  ##STR87##                                                1080  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR88##                                                1081  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR89##                                                1082  n-butyl                                                                            n-butyl                                                                            OH  H  2-pyridyl                                                 1083  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR90##                                                1084  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR91##                                                1085  n-butyl                                                                            n-butyl                                                                            OH  H  thiophen-3-yl                                             1086  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR92##                                                1087  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR93##                                                1088  ethyl                                                                              n-butyl                                                                            OH  H  3,4-methylenedioxyphenyl                                  1089  ethyl                                                                              n-butyl                                                                            OH  H  4-methoxyphenyl                                           1090  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR94##                                                1091  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR95##                                                1092  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR96##                                                1093  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR97##                                                1094  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR98##                                                1095  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR99##                                                1096  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR100##                                               1097  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR101##                                               1098  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR102##                                               1099  ethyl                                                                              n-butyl                                                                            OH  H  4-methoxyphenyl                                           1100  n-butyl                                                                            n-butyl                                                                            OH  H  4-methoxyphenyl                                           1101  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR103##                                               1102  n-butyl                                                                            n-butyl                                                                            OH  H  3-carboxymethylphenyl                                     1103  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR104##                                               1104  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR105##                                               1105  n-butyl                                                                            n-butyl                                                                            OH  H  5-piperonyl                                               1106  n-butyl                                                                            n-butyl                                                                            OH  H  3-hydroxyphenyl                                           1107  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR106##                                               1108  n-butyl                                                                            n-butyl                                                                            OH  H  3-pyridyl                                                 1109  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR107##                                               1110  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR108##                                               1111  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR109##                                               1112  n-butyl                                                                            n-butyl                                                                            OH  H  4-pyridyl                                                 1113  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR110##                                               1114  n-butyl                                                                            n-butyl                                                                            OH  H  3-methoxyphenyl                                           1115  n-butyl                                                                            n-butyl                                                                            OH  H  4-fluorophenyl                                            1116  ethyl                                                                              n-butyl                                                                            OH  H  3-tolyl                                                   1117  ethyl                                                                              n-butyl                                                                            OH  H                                                                                  ##STR111##                                               1118  ethyl                                                                              n-butyl                                                                            OH  H  3-fluoro-4-hydroxyphenyl                                  1119  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR112##                                               1120  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR113##                                               1121  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR114##                                               1122  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR115##                                               1123  n-butyl                                                                            n-butyl                                                                            OH  H  phenyl                                                    1124  n-butyl                                                                            n-butyl                                                                            OH  H  3-methoxyphenyl                                           1125  n-butyl                                                                            n-butyl                                                                            OH  H  3-chloro-4-methoxyphenyl                                  1126  ethyl                                                                              n-butyl                                                                            OH  H                                                                                  ##STR116##                                               1127  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR117##                                               1128  n-butyl                                                                            n-butyl                                                                            OH  H  3-fluoro-4-hydroxyphenyl                                  1129  n-butyl                                                                            n-butyl                                                                            OH  H  4-fluorophenyl                                            1130  n-butyl                                                                            n-butyl                                                                            OH  H  3-chloro-4-fluorophenyl                                   1131  ethyl                                                                              n-butyl                                                                            OH  H  4-methoxyphenyl                                           1132  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR118##                                               1133  n-butyl                                                                            n-butyl                                                                            OH  H  4-cyanomethylphenyl                                       1134  ethyl                                                                              n-butyl                                                                            OH  H                                                                                  ##STR119##                                               1135  n-butyl                                                                            n-butyl                                                                            OH  H  3,4-dimethoxyphenyl                                       1136  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR120##                                               1137  n-butyl                                                                            n-butyl                                                                            OH  H  4-fluorophenyl                                            1138  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR121##                                               1139  n-butyl                                                                            n-butyl                                                                            OH  H  3,4-difluorophenyl                                        1140  n-butyl                                                                            n-butyl                                                                            OH  H  3-methoxyphenyl                                           1141  n-butyl                                                                            n-butyl                                                                            OH  H  4-fluorophenyl                                            1142  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR122##                                               1143  n-butyl                                                                            n-butyl                                                                            H   OH H                                                         1144  n-butyl                                                                            n-butyl                                                                            OH  H  5-piperonyl                                               1145  n-butyl                                                                            n-butyl                                                                            OH  H  4-methoxyphenyl                                           1146  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR123##                                               1147  n-butyl                                                                            n-butyl                                                                            OH  H  3-methoxyphenyl                                           1148  n-butyl                                                                            n-butyl                                                                            OH  H  4-fluorophenyl                                            1149  n-butyl                                                                            n-butyl                                                                            OH  H  4-fluorophenyl                                            1150  n-butyl                                                                            n-butyl                                                                            OH  H  3-methoxyphenyl                                           1151  n-butyl                                                                            ethyl                                                                              OH  H  3-fluoro-4-methoxyphenyl                                  1152  n-butyl                                                                            n-butyl                                                                            OH  H  phenyl                                                    1153  n-butyl                                                                            n-butyl                                                                            OH  H  4-fluorophenyl                                            1154  n-butyl                                                                            n-butyl                                                                            OH  H  3-methoxyphenyl                                           1155  n-butyl                                                                            n-butyl                                                                            OH  H  4-fluorophenyl                                            1156  n-butyl                                                                            n-butyl                                                                            OH  H  4-fluorophenyl                                            1157  n-butyl                                                                            n-butyl                                                                            OH  H  4-fluorophenyl                                            1158  n-butyl                                                                            n-butyl                                                                            OH  H  4-pyridinyl, hydrochloride salt                           1159  n-butyl                                                                            ethyl                                                                              OH  H  phenyl                                                    1160  n-butyl                                                                            n-butyl                                                                            OH  H  4-fluorophenyl                                            1161  n-butyl                                                                            n-butyl                                                                            OH  H  3,5-dichloro-4-methoxyphenyl                              1162  n-butyl                                                                            n-butyl                                                                            OH  H  phenyl                                                    1163  n-butyl                                                                            n-butyl                                                                            OH  H  3-(dimethylamino)phenyl                                   1164  n-butyl                                                                            n-butyl                                                                            OH  H  4-pyridinyl                                               1165  n-butyl                                                                            n-butyl                                                                            OH  H  3-fluoro-4-methoxyphenyl                                  1166  n-butyl                                                                            n-butyl                                                                            OH  H  3-hydroxyphenyl                                           1167  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR124##                                               1168  n-butyl                                                                            n-butyl                                                                            OH  H  4-fluoroxyphenyl                                          1169  n-butyl                                                                            n-butyl                                                                            OH  H  phenyl                                                    1170  n-butyl                                                                            n-butyl                                                                            OH  H  3-methoxyphenyl                                           1171  n-butyl                                                                            n-butyl                                                                            OH  H  4-(trifluoromethylsulfonyloxy)phenyl                      1172  n-butyl                                                                            n-butyl                                                                            OH  H  4-pyridinyl                                               1173  n-butyl                                                                            n-butyl                                                                            OH  H  4-fluorophenyl                                            1174  ethyl                                                                              n-butyl                                                                            OH  H  3-methoxyphenyl                                           1175  ethyl                                                                              n-butyl                                                                            OH  H  3-methoxyphenyl                                           1176  n-butyl                                                                            n-butyl                                                                            OH  H  4-fluorophenyl                                            1177  n-butyl                                                                            n-butyl                                                                            OH  H  3-methoxyphenyl                                           1178  n-butyl                                                                            n-butyl                                                                            OH  H  3-(trifluoromethylsulfonyloxy)phenyl                      1179  n-butyl                                                                            n-butyl                                                                            OH  H  phenyl                                                    1180  n-butyl                                                                            n-butyl                                                                            OH  H  phenyl                                                    1181  n-butyl                                                                            n-butyl                                                                            OH  H  4-fluorophenyl                                            1182  n-butyl                                                                            n-butyl                                                                            OH  H  4-(dimethylamino)phenyl                                   1183  n-butyl                                                                            n-butyl                                                                            OH  H  3-methoxyphenyl                                           1184  n-butyl                                                                            n-butyl                                                                            OH  H  4-fluorophenyl                                            1185  n-butyl                                                                            n-butyl                                                                            OH  H  4-fluorophenyl                                            1186  n-butyl                                                                            n-butyl                                                                            OH  H  phenyl                                                    1187  n-butyl                                                                            n-butyl                                                                            OH  H  4-fluorophenyl                                            1188  n-butyl                                                                            n-butyl                                                                            OH  H  4-methoxyphenyl                                           1189  n-butyl                                                                            n-butyl                                                                            OH  H  3-4-difluorophenyl                                        1190  n-butyl                                                                            n-butyl                                                                            OH  H  2-bromophenyl                                             1191  n-butyl                                                                            n-butyl                                                                            OH  H  4-(dimethylamino)phenyl                                   1192  n-butyl                                                                            n-butyl                                                                            OH  H  3-(dimethylamino)phenyl                                   1193  n-butyl                                                                            n-butyl                                                                            OH  H  4-(2-(2-methylpropyl))phenyl                              1194  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR125##                                               1195  n-butyl                                                                            n-butyl                                                                            OH  H  4-methoxyphenyl                                           1196  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR126##                                               1197  n-butyl                                                                            ethyl                                                                              R3 +  R4 =  oxo                                                                    R3 +  R4 =  oxo                                                                   phenyl                                                    1198  n-butyl                                                                            n-butyl                                                                            OH  H  4-(pyridinyl-N-oxide)                                     1199  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR127##                                               1200  n-butyl                                                                            n-butyl                                                                            H   OH H                                                         1201  n-butyl                                                                            n-butyl                                                                            OH  H  H                                                         1202  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR128##                                               1203  n-butyl                                                                            n-butyl                                                                            OH  H  5-piperazinyl                                             1204  n-butyl                                                                            n-butyl                                                                            OH  H  4-fluorophenyl                                            1205  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR129##                                               1206  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR130##                                               1207  n-butyl                                                                            n-butyl                                                                            OH  H  3,5-dichlorophenyl                                        1208  n-butyl                                                                            n-butyl                                                                            OH  H  4-methoxyphenyl                                           1209  n-butyl                                                                            n-butyl                                                                            acetoxy                                                                            H  phenyl                                                    1210  n-butyl                                                                            n-butyl                                                                            OH  H  2-(dimethylamino)phenyl                                   1211  ethyl                                                                              n-butyl                                                                            OH  H                                                                                  ##STR131##                                               1212  n-butyl                                                                            n-butyl                                                                            OH  H  4-methoxyphenyl                                           1213  n-butyl                                                                            ethyl                                                                              H   OH H                                                         1214  n-butyl                                                                            ethyl                                                                              OH  H  phenyl                                                    1215  n-butyl                                                                            n-butyl                                                                            OH  H  4-methoxyphenyl                                           1216  ethyl                                                                              n-butyl                                                                            OH  H  5-piperonyl                                               1217  n-butyl                                                                            n-butyl                                                                            OH  H  4-carboxyphenyl                                           1218  n-butyl                                                                            n-butyl                                                                            OH  H  4-methoxyphenyl                                           1219  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR132##                                               1220  n-butyl                                                                            n-butyl                                                                            OH  H  3-methoxyphenyl                                           1221  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR133##                                               1222  n-butyl                                                                            n-butyl                                                                            OH  H  3-methoxyphenyl                                           1223  n-butyl                                                                            n-butyl                                                                            OH  H  phenyl                                                    1224  n-butyl                                                                            n-butyl                                                                            OH  H  3-nitrophenyl                                             1225  n-butyl                                                                            ethyl                                                                              OH  H  3-methylphenyl                                            1226  ethyl                                                                              n-butyl                                                                            OH  H  5-piperonyl                                               1227  n-butyl                                                                            n-butyl                                                                            OH  H  4-fluorophenyl                                            1228  n-butyl                                                                            n-butyl                                                                            OH  H  2-pyrrolyl                                                1229  n-butyl                                                                            n-butyl                                                                            OH  H  3-chloro-4-hydroxyphenyl                                  1230  n-butyl                                                                            n-butyl                                                                            OH  H  phenyl                                                    1231  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR134##                                               1232  n-butyl                                                                            n-butyl                                                                            H   OH 3-thiophenyl                                              1233  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR135##                                               1234  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR136##                                               1235  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR137##                                               1236  n-butyl                                                                            n-butyl                                                                            OH  H  4-(bromomethyl)phenyl                                     1237  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR138##                                               1238  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR139##                                               1239  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR140##                                               1240  n-butyl                                                                            n-butyl                                                                            OH  H  4-methoxy-3-methylphenyl                                  1241  n-butyl                                                                            n-butyl                                                                            OH  H  3-(dimethylaminomethyl)phenyl                             1242  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR141##                                               1243  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR142##                                               1244  n-butyl                                                                            n-butyl                                                                            OH  H  3-methoxyphenyl                                           1245  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR143##                                               1246  n-butyl                                                                            n-butyl                                                                            OH  H  3-(bromomethyl)phenyl                                     1247  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR144##                                               1248  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR145##                                               1249  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR146##                                               1250  n-butyl                                                                            n-butyl                                                                            OH  H  3-(dimethylamino)phenyl                                   1251  n-butyl                                                                            n-butyl                                                                            OH  H  1-naphthyl                                                1252  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR147##                                               1253  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR148##                                               1254  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR149##                                               1255  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR150##                                               1256  n-butyl                                                                            n-butyl                                                                            OH  H  3-nitrophenyl                                             1257  n-butyl                                                                            n-butyl                                                                            OH  H  phenyl                                                    1258  n-butyl                                                                            n-butyl                                                                            OH  H  4-fluorophenyl                                            1259  ethyl                                                                              n-butyl                                                                            H   OH H                                                         1260  ethyl                                                                              n-butyl                                                                            OH  H  3-hydroxyphenyl                                           1261  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR151##                                               1262  n-butyl                                                                            n-butyl                                                                            OH  H  2-thiophenyl                                              1263  n-butyl                                                                            n-butyl                                                                            OH  H  5-piperonyl                                               1264  n-butyl                                                                            n-butyl                                                                            OH  H  4-fluorophenyl                                            1265  n-butyl                                                                            n-butyl                                                                            OH  H  4-fluorophenyl                                            1266  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR152##                                               1267  n-butyl                                                                            ethyl                                                                              OH  H  5-piperonyl                                               1268  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR153##                                               1269  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR154##                                               1270  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR155##                                               1271  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR156##                                               1272  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR157##                                               1273  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR158##                                               1274  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR159##                                               1275  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR160##                                               1276  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR161##                                               1277  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR162##                                               1278  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR163##                                               1279  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR164##                                               1280  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR165##                                               1281  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR166##                                               1282  ethyl                                                                              n-butyl                                                                            OH  H  3-fluoro-4-methoxyphenyl                                  1283  n-butyl                                                                            n-butyl                                                                            OH  H  4-hydroxymethylphenyl                                     1284  n-butyl                                                                            n-butyl                                                                            OH  H  4-fluorophenyl                                            1285  n-butyl                                                                            ethyl                                                                              OH  H  phenyl                                                    1286  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR167##                                               1287  n-butyl                                                                            ethyl                                                                              OH  H  4-hydroxyphenyl                                           1288  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR168##                                               1289  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR169##                                               1290  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR170##                                               1291  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR171##                                               1292  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR172##                                               1293  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR173##                                               1294  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR174##                                               1295  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR175##                                               1296  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR176##                                               1297  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR177##                                               1298  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR178##                                               1299  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR179##                                               1300  n-butyl                                                                            ethyl                                                                              OH  H  H                                                         1301  n-butyl                                                                            n-butyl                                                                            OH  H  3-methoxyphenl                                            1302  n-butyl                                                                            n-butyl                                                                            OH  H  3-hydroxyphenyl                                           1303  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR180##                                               1304  n-butyl                                                                            n-butyl                                                                            OH  H  3-methoxyphenyl                                           1305  n-butyl                                                                            n-butyl                                                                            OH  H  4-fluorophenyl                                            1306  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR181##                                               1307  n-butyl                                                                            n-butyl                                                                            OH  H  H                                                         1308  ethyl                                                                              n-butyl                                                                            OH  H                                                                                  ##STR182##                                               1309  n-butyl                                                                            n-butyl                                                                            OH  H  4-methoxyphenyl                                           1310  ethyl                                                                              n-butyl                                                                            OH  H  phenyl                                                    1311  n-butyl                                                                            ethyl                                                                              OH  H  phenyl                                                    1312  n-butyl                                                                            ethyl                                                                              OH  H  phenyl                                                    1313  n-butyl                                                                            ethyl                                                                              OH  H  phenyl                                                    1314  ethyl                                                                              n-butyl                                                                            OH  H  phenyl                                                    1315  ethyl                                                                              n-butyl                                                                            OH  H  phenyl                                                    1316  n-butyl                                                                            ethyl                                                                              OH  H  phenyl                                                    1317  n-butyl                                                                            ethyl                                                                              OH  H  phenyl                                                    1318  ethyl                                                                              n-butyl                                                                            OH  H  phenyl                                                    1319  ethyl                                                                              n-butyl                                                                            OH  H  3-methoxyphenyl                                           1320  ethyl                                                                              n-butyl                                                                            OH  H  phenyl                                                    1321  n-butyl                                                                            ethyl                                                                              OH  H  phenyl                                                    1322  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR183##                                               1323  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR184##                                               1324  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR185##                                               1325  n-butyl                                                                            n-butyl                                                                            OH  H  4-((diethylamino)methyl)phenyl                            1326  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR186##                                               1327  n-butyl                                                                            n-butyl                                                                            OH  H  3-fluoro-4-hydroxy-5-iodophenyl                           1328  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR187##                                               1329  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR188##                                               1330  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR189##                                               1331  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR190##                                               1332  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR191##                                               1333  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR192##                                               1334  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR193##                                               1335  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR194##                                               1336  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR195##                                               1337  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR196##                                               1338  n-butyl                                                                            n-butyl                                                                            OH  H  4-methoxyphenyl                                           1339  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR197##                                               1340  n-butyl                                                                            ethyl                                                                              OH  H  5-piperonyl                                               1341  n-butyl                                                                            n-butyl                                                                            acetoxy                                                                            H  3-methoxyphenyl                                           1342  n-butyl                                                                            n-butyl                                                                            OH  H  5-piperonyl                                               1343  ethyl                                                                              n-butyl                                                                            OH  H  phenyl                                                    1344  n-butyl                                                                            n-butyl                                                                            OH  H  3-fluoro-4-methoxyphenyl                                  1345  ethyl                                                                              n-butyl                                                                            OH  H  phenyl                                                    1346  ethyl                                                                              n-butyl                                                                            OH  H  phenyl                                                    1347  n-butyl                                                                            n-butyl                                                                            OH  H  3-fluoro-4-methoxyphenyl                                  1348  isobutyl                                                                           isobutyl                                                                           OH  H  phenyl                                                    1349  ethyl                                                                              n-butyl                                                                            OH  H  phenyl                                                    1350  n-butyl                                                                            n-butyl                                                                            OH  H  3-fluoro-4-methoxyphenyl                                  1351  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR198##                                               1352  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR199##                                               1353  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR200##                                               1354  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR201##                                               1355  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR202##                                               1356  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR203##                                               1357  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR204##                                               1358  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR205##                                               1359  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR206##                                               1360  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR207##                                               1361  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR208##                                               1362  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR209##                                               1363  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR210##                                               1364  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR211##                                               1365  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR212##                                               1366  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR213##                                               1367  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR214##                                               1368  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR215##                                               1369  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR216##                                               1370  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR217##                                               1371  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR218##                                               1372  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR219##                                               1373  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR220##                                               1374  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR221##                                               1375  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR222##                                               1376  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR223##                                               1377  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR224##                                               1378  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR225##                                               1379  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR226##                                               1380  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR227##                                               1381  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR228##                                               1382  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR229##                                               1383  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR230##                                               1384  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR231##                                               1385  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR232##                                               1386  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR233##                                               1387  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR234##                                               1388  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR235##                                               1389  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR236##                                               1390  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR237##                                               1391  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR238##                                               1392  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR239##                                               1393  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR240##                                               1394  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR241##                                               1395  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR242##                                               1396  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR243##                                               1397  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR244##                                               1398  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR245##                                               1399  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR246##                                               1400  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR247##                                               1401  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR248##                                               1402  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR249##                                               1403  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR250##                                               1404  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR251##                                               1405  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR252##                                               1406  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR253##                                               1407  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR254##                                               1408  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR255##                                               1409  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR256##                                               1410  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR257##                                               1411  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR258##                                               1412  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR259##                                               1413  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR260##                                               1414  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR261##                                               1415  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR262##                                               1416  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR263##                                               1417  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR264##                                               1418  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR265##                                               1419  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR266##                                               1420  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR267##                                               1421  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR268##                                               1422  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR269##                                               1423  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR270##                                               1424  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR271##                                               1425  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR272##                                               1426  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR273##                                               1427  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR274##                                               1428  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR275##                                               1429  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR276##                                               1430  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR277##                                               1431  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR278##                                               1432  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR279##                                               1433  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR280##                                               1434  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR281##                                               1435  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR282##                                               1436  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR283##                                               1437  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR284##                                               1438  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR285##                                               1439  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR286##                                               1440  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR287##                                               1441  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR288##                                               1442  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR289##                                               1443  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR290##                                               1444  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR291##                                               1445  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR292##                                               1446  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR293##                                               1447  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR294##                                               1448  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR295##                                               1449  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR296##                                               1450  n-butyl                                                                            n-butyl                                                                            OH  H  phenyl                                                    1451  n-butyl                                                                            n-butyl                                                                            OH  H                                                                                  ##STR297##                                               __________________________________________________________________________     Compound                                                                       Number   R.sup.b   (R.sup.X).sub.q                                             __________________________________________________________________________      101     H                                                                                         ##STR298##                                                  102     H         7-trimethylammonium iodide                                   103     H         7-trimethylammonium iodide                                   104     H         7-dimethylamino                                              105     H         7-methanesulfonamido                                         106     H         7-(2'-bromoacetamido)                                        107     H         7-amino                                                      108     H         7-(hexylamido)                                               109     H         7-amino                                                      110     H         7-acetamido                                                  111     H         7-amino                                                      112     H         7-amino                                                      113     H         7-amino                                                      114     H         7-amino                                                      115     H         7-(O-benzylcarbamato)                                        116     H         7-(O-benzylcarbamato)                                        117     H         7-(O-benzylcarbamato)                                        118     H         7-(O-benzylcarbamato)                                        119     H         7-(O-tert-butylcarbamato)                                    120     H         7-(O-benzylcarbamato)                                        121     H         7-amino                                                      122     H         7-amino                                                      123     H         7-hexylamino                                                 124     H         7-(hexylamino)                                               125     H                                                                                         ##STR299##                                                  126     H         7-(O-benzylcarbamato)                                        127     H         7-amino                                                      128     H         7-(O-benzylcarbamato)                                        129     H         7-amino                                                      131     H                                                                                         ##STR300##                                                  132     H                                                                                         ##STR301##                                                  133     H         8-(hexyloxy)                                                 134     H                                                                                         ##STR302##                                                  135     H                                                                                         ##STR303##                                                  136     H         8-hydroxy                                                    137     H                                                                                         ##STR304##                                                  138     H         8-acetoxy                                                    139     H                                                                                         ##STR305##                                                  140                                                                            141                                                                            142     3-methoxy-                                                                               7-methylmercapto                                                     phenyl                                                                 143     H         7-methylmercapto                                             144     H         7-(N-azetidinyl)                                             262     H         7-methoxy                                                    263     3-methoxy-                                                                               7-methoxy                                                            phenyl                                                                 264     H         7-methoxy                                                    265     3-        7-methoxy                                                            trifluoro-                                                                     methyl-                                                                        phenyl                                                                 266     H         7-hydroxy                                                    267     H         7-methoxy                                                    268     H         7-methoxy                                                    269     4-fluoro- 7-methoxy                                                            phenyl                                                                 270     H         7-hydroxy                                                    271     H         7-bromo                                                      272     3-methoxy-                                                                               7-bromo                                                              phenyl                                                                 273     4-fluoro- 7-fluoro                                                             phenyl                                                                 274     H         7-fluoro                                                     275     3-methoxy-                                                                               7-fluoro                                                             phenyl                                                                 276     H         7-fluoro                                                     277     H         7-methoxy                                                    278     H         7-methoxy                                                    279     H         7-methoxy                                                    280     H         7-methoxy                                                    281     H         7-methylmercapto                                             282     H         7-methyl                                                     283     4-fluoro- 7-methyl                                                             phenyl                                                                 284     H         7-(4'-morpholino)                                            286     H         7-(O-benzylcarbamato)                                        287     H         7-amino                                                      288     H         7-amino                                                      289     H         7-amino                                                      290     H         7-amino                                                      291     H         7-(O-benzylcarbamato)                                        292     H         7-amino                                                      293     H         7-benzylamino                                                294     H         7-dimethylamino                                              295     H         7-amino                                                      296     H         7-amino                                                     1000     H         7-dimethylamino                                             1001     H         7-dimethylamino                                             1002     H         7-dimethylamino                                             1003     H         7-dimethylamino                                             1004     H         7-dimethylamino                                             1005     H         7-dimethylamino                                             1006     H         7-dimethylamino                                             1007     H         7-dimethylamino                                             1008     H         7-dimethylamino                                             1009     H         7-dimethylamino                                             1010     H         7-dimethylamino                                             1011     H         7-dimethylamino                                             1012     H         7-dimethylanino; 9-methoxy                                  1013     H         7-dimethylamino                                             1014     H         7-dimethylamino; 9-methoxy                                  1015     H         7-dimethylamino                                             1016     H         7-dimethylamino                                             1017     H         7-dimethylamino                                             1018     H         7-dimethylamino                                             1019     H         7-dimethylamino                                             1020     H         7-dimethylamino                                             1021     H         7-dimethylamino                                             1022     H         7-dimethylamino                                             1023     H         7-dimethylamino                                             1024     H         7-dimethylamino                                             1025     H         7-dimethylamino                                             1026     H         7-dimethylamino                                             1027     H         7-dimethylamino                                             1028     H         7-dimethylamino                                             1029     H         7-dimethylamino                                             1030     H         7-dimethylamino                                             1031     H         7-dimethylamino                                             1032     H         7-dimethylamino                                             1033     H         7-dimethylamino                                             1034     H         7-dimethylamino                                             1035     H         7-dimethylamino                                             1036     H         7-dimethylamino                                             1037     H         7-dimethylamino                                             1038     H         7-dimethylamino                                             1039     H         7-dimethylamino                                             1040     H         7-dimethylamino                                             1041     H         7-dimethylamino                                             1042     H         7-dimethylamino                                             1043     H         7-dimethylamino                                             1044     H         7-dimethylamino                                             1045     H         7-dimethylamino                                             1046     H         7-dimethylamino                                             1047     H         7-dimethylamino                                             1048     H         7-dimethylamino                                             1049     H         7-dimethylamino                                             1050     H         7-dimethylamino                                             1051     H         7-dimethylamino                                             1052     H         7-dimethylamino                                             1053     H         7-dimethylamino                                             1054     H         7-dimethylamino                                             1055     H         7-dimethylamino                                             1056     H         7-dimethylamino                                             1057     H         7-dimethylamino                                             1058     H         7-dimethylamino                                             1059     H         7-dimethylamino                                             1060     H         7-dimethylamino                                             1061     H         7-methylamino                                               1062     H         7-methylamino                                               1063     H         7-methylamino                                               1064     H         7-methylamino                                               1065     H         7-methylamino                                               1066     H         7-dimethylamino                                             1067     H         9-dimethylamino                                             1068     H         7-dimethylamino                                             1069     H         7-dimethylamino;                                                               9-dimethylamino                                             1070     H         7-dimethylamino                                             1071     H         7-dimethylamino                                             1072     H         7-dimethylamino                                             1073     H         7-dimethylamino                                             1074     H         7-dimethylamino                                             1075     H         7-dimethylamino; 9-dimethylamino                            1076     H         7-dimethylamino                                             1077     H         7-dimethylamino                                             1078     H         7-dimethylamino                                             1079     H         7-dimethylamino                                             1080     H         7-dimethylamino                                             1081     H         7-dimethylamino                                             1082     H         7-dimethylamino                                             1083     H         7-dimethylamino                                             1084     H         7-dimethylamino                                             1085     H         7-dimethylamino                                             1086     H         7-dimethylamino                                             1087     H         7-dimethylamino                                             1088     H         7-dimethylamino                                             1089     H         7-dimethylamino                                             1090     H         7-dimethylamino                                             1091     H         7-dimethylamino                                             1092     H         7-dimethylamino                                             1093     H         7-dimethylamino                                             1094     H         7-dimethylamino                                             1095     H         7-dimethylamino                                             1096     H         7-dimethylamino                                             1097     H         7-dimethylamino                                             1098     H         7-dimethylamino                                             1099     H         7-dimethylamino                                             1100     H         7-dimethylamino                                             1101     H         7-dimethylamino                                             1102     H         7-dimethylamino                                             1103     H         7-dimethylamino                                             1104     H         7-dimethylamino                                             1105     H         7-dimethylamino                                             1106     H         7-dimethylamino                                             1107     H         7-dimethylamino                                             1108     H         7-dimethylamino                                             1109     H         7-dimethylamino                                             1110     H         7-dimethylamino                                             1111     H         7-dimethylamino                                             1112     H         7-dimethylamino                                             1113     H         7-dimethylamino                                             1114     H         7-methylamino                                               1115     H         7-dimethylamino                                             1116     H         7-dimethylamino                                             1117     H         7-diwethylamino                                             1118     H         7-dimethylamino                                             1119     H         7-dimetnylamino                                             1120     H         7-dimethylamino                                             1121     H         7-dimethylamino                                             1122     H         7-dimethylamino                                             1123     H         7-dimethylamino                                             1124     H         7-dimethylamino                                             1125     H         7-dimethylamino                                             1126     H         7-dimethylamino                                             1127     H         7-dimethylamino                                             1128     H         7-dimethylamino                                             1129     H         9-dimethylamino                                             1130     H         7-dimethylamino                                             1131     H         7-dimethylamino                                             1132     H         7-dimethylamino                                             1133     H         7-dimethylamino                                             1134     H         7-dimethylamino                                             1135     H         7-dimethylamino                                             1136     H         7-dimethylamino                                             1137     H         9-(2',2'-dimethylhydrazino)                                 1138     H         7-dimethylamino                                             1139     H         7-dimethylamino                                             1140     H         7-(2',2'-dimethylhydrazino)                                 1141     H         7-ethylmethylamino                                          1142     H         7-dimethylamino                                             1143     3-fluoro- 7-dimethylamino                                                      4-methoxy-                                                                     phenyl                                                                1144     H         7-dimethylamino                                             1145     H         9-dimethylamino                                             1146     H         7-dimethylamino                                             1147     H         7-diethylamino                                              1148     H         7-dimethylsulfonium, fluoride salt                          1149     H         7-ethylamino                                                1150     H         7-ethylmethylamino                                          1151     H         7-dimethylamino                                             1152     H         7-(ethoxymethyl) methylamino                                1153     H         7-methylamino                                               1154     H         9-methoxy                                                   1155     H         7-methyl                                                    1156     H         7-methylmercapto                                            1157     H         7-fluoro;                                                                      9-dimethylamino                                             1158     H         7-methoxy                                                   1159     H         7-dimethylamino                                             1160     H         7-diethylamino                                              1161     H         7-dimethylamino                                             1162     H         7-dimethylamino                                             1163     H         7-methoxy                                                   1164     H         7-methoxy                                                   1165     H         7-trimethylammonium iodide                                  1166     H         7-trimethylammonium iodide                                  1167     H         7-dimethylamino                                             1168     H         7-trimethylammonium iodide                                  1169     H         8-dimethylamino                                             1170     H         7-ethylpropylamino                                          1171     H         7-dimethylamino                                             1172     H         7-methoxy                                                   1173     H         7-ethylpropylamino                                          1174     H         7-phenyl                                                    1175     H         7-methylsulfonyl                                            1176     H         9-fluoro                                                    1177     H         7-butylmethylamino                                          1178     H         7-dimethylamino                                             1179     H         7-methoxy                                                   1180     H         7-trimethylammonium iodide                                  1181     H         7-butylmethylamino                                          1182     H         7-methoxy                                                   1183     H         7-fluoro                                                    1184     H         7-fluoro; 9-fluoro                                          1185     H         7-fluoro                                                    1186     H         7-fluoro; 9-fluoro                                          1187     H         7-methyl                                                    1188     H         7-trimethylammonium iodide                                  1189     H         7-trimethylammonium iodide                                  1190     H         7-bromo                                                     1191     H         7-hydroxy                                                   1192     H         7-hydroxy                                                   1193     H         7-dimethylamino                                             1194     H         7-dimethylamino                                             1195     H         7-(4'-methylpiperazin-1-yl)                                 1196     H         7-methoxy                                                   1197     H         7-(N-methylformamido)                                       1198     H         7-methoxy                                                   1199     H         7-dimethylamino                                             1200     phenyl    7-dimethylamino                                             1201     H         7-methyl                                                    1202     H         7-methoxy                                                   1203     H         7-(4'-tert-butylphenyl)                                     1204     H         7-methoxy                                                   1205     H         7-dimethylamino                                             1206     H         7-dimethylamino                                             1207     H         7-dimethylamino                                             1208     H         7-dimethylamino                                             1209     H         7-dimethylphenyl                                            1210     H         7-dimethylamino                                             1211     H         7-dimethylamino                                             1212     H         9-(4'-morpholino)                                           1213     3-fluoro- 7-dimethylamino                                                      4-methoxy-                                                                     phenyl                                                                1214     H         7-(N-methylformamido)                                       1215     H         9-methylmercapto                                            1216     H         7-bromo                                                     1217     H         7-dimethylamino                                             1218     H         9-methylsulfonyl                                            1219     H         7-dimethylamino                                             1220     H         7-isopropylamino                                            1221     H         7-dimethylamino                                             1222     H         7-ethylamlno                                                1223     H         8-bromo;                                                                       7-methylamino                                               1224     H         7-fluoro                                                    1225     H         7-dimethylamino                                             1226     H         7-bromo                                                     1227     H         7-(tert-butylamino                                          1228     H         8-bromo;                                                                       7-dimethylamino                                             1229     H         7-dimethylamino                                             1230     H         9-dimethylamino;                                                               7-fluoro                                                    1231     H         7-dimethylamino                                             1232     H         9-dimethylamino                                             1233     H         7-dimethylamino                                             1234     H         7-dimethylamino                                             1235     H         7-dimethylamino                                             1236     H         7-dimethylamino                                             1237     H         7-dimethylamino                                             1238     H         7-dimethylamino                                             1239     H         7-dimethylamino                                             1240     H         7-dimethylamino                                             1241     H         7-dimethylamino                                             1242     H         7-dimethylamino                                             1243     H         7-dimethylamino                                             1244     H         7-(1'-methylhydrazido)                                      1245     H         7-dimethylamino                                             1246     H         7-dimethylamino                                             1247     H         7-dimethylamino                                             1248     H         7-dimethylamino                                             1249     H         7-dimethylamino                                             1250     H         7-dimethylamino                                             1251     H         7-dimethylamino                                             1252     H         7-dimethylamino                                             1253     H         7-dimethylamino                                             1254     H         7-dimethylamino                                             1255     H         7-dimethylamino                                             1256     H         7-dimethylamino                                             1257     H         8-bromo; 7-dimethylamino                                    1258     H         9-(tert-butylamino)                                         1259     phenyl    7-dimethylamino                                             1260     H         7-dimethylamino                                             1261     H         7-dimethylamino                                             1262     H         7-dimethylamino                                             1263     H         7-bromo                                                     1264     H         7-isopropylamino                                            1265     H         9-isopropylamino                                            1266     H         7-dimethylamino                                             1267     H         7-carboxy, methyl ester                                     1268     H         7-dimethylamino                                             1269     H         7-dimethylamino                                             1270     H         7-dimethylamino                                             1271     H         7-dimethylamino                                             1272     H         7-dimethylamino                                             1273     H         7-dimethylamino                                             1274     H         7-dimethylamino                                             1275     H         7-dimethylamino                                             1276     H         7-dimethylamino                                             1277     H         7-dimethylamino                                             1278     H         7-dimethylamino                                             1279     H         7-dimethylamino                                             1280     H         7-dimethylamino                                             1281     H         7-dimethylamino                                             1282     H         7-trimethylammonium iodide                                  1283     H         7-dimethylamino                                             1284     H         9-ethylamino                                                1285     H         7-dimethylamino                                             1286     H         7-dimethylamino                                             1287     H         7-dimethylamino                                             1288     H         7-dimethylamino                                             1289     H         7-dimethylamino                                             1290     H         7-dimethylamino                                             1291     H         7-dimethylamino                                             1292     H         7-dimethylamnio                                             1293     H         7-dimethylamino                                             1294     H         7-dimethylamino                                             1295     H         7-dimethylamino                                             1296     H         7-dimethylamino                                             1297     H         7-dimethylamino                                             1298     H         7-dimethylamino                                             1299     H         7-dimethylamino                                             1300     phenyl    7-dimethylamino                                             1301     H         7-trimethylammonium iodide                                  1302     H         9-hydroxy                                                   1303     H         7-dimethylamino                                             1304     H         7-tert-butylamino                                           1305     H         9-methylamino                                               1306     H         7-dimethylamino                                             1307     4-methoxy-                                                                               9-(4'-morpholino)                                                    phenyl                                                                1308     H         7-dimethylamino                                             1309     H         9-fluoro                                                    1310     H         7-amino                                                     1311     H         7-(hydroxylamino)                                           1312     H         8-hexyloxy                                                  1313     H         8-ethoxy                                                    1314     H         7-(hydroxylamino)                                           1315     H         7-(hexyloxy)                                                1316     H         8-hydroxy                                                   1317     H                                                                                         ##STR306##                                                 1318     H         7-dimethylamino                                             1319     H         7-fluoro                                                    1320     H         7-amino                                                     1321     H                                                                                         ##STR307##                                                 1322     H         7-dimethylamino                                             1323     H         7-dimethylamino                                             1324     H         7-dimethylamino                                             1325     H         7-dimethylamino                                             1326     H         7-dimethylamino                                             1327     H         7-dimethylamino                                             1328     H         7-dimethylamino                                             1329     H         7-dimethylamino                                             1330     H         7-dimethylamino                                             1331     H         7-dimethylamino                                             1332     H         7-dimethylamino                                             1333     H         7-dimethylamino                                             1334     H         7-dimethylamino                                             1335     H         7-dimethylamino                                             1336     H         7-dimethyla.mino                                            1337     H         7-dimethylamino                                             1338     H         7-(4'-methylpiperazinyl)                                    1339     H         7-dimethylamino                                             1340     H         7-methyl                                                    1341     H         7-dimethylamino                                             1342     H         7-(4-fluorophenyl)                                          1343     H         7-amino                                                     1344     H         7-dimethylamino                                             1345     H         7-trimethylammonium iodide                                  1346     H                                                                                         ##STR308##                                                 1347     H         7-dimethylamino                                             1348     H         7-dimethylamino                                             1349     H         7-dimethylamino                                             1350     H         7-trimethylammonium iodide                                  1351     H         7-dimethylamino                                             1352     H         7-dimethylamino                                             1353     H         7-dimethylamino                                             1354     H         7-dimethylamino                                             1355     H         7-dimethylamino                                             1356     H         7-dimethylamino                                             1357     H         7-dimethylamino                                             1358     H         7-dimethylamino                                             1359     H         7-dimethylamino                                             1360     H         7-dimethylamino                                             1361     H         7-dimethylamino                                             1362     H         7-dimethylamino                                             1363     H         7-dimethylamino                                             1364     H         7-dimethylamino                                             1365     H         7-dimethylamino                                             1366     H         7-dimethylamino                                             1367     H         7-dimethylamino                                             1368     H         7-dimethylamino                                             1369     H         7-dimethylamino                                             1370     H         7-dimethylamino                                             1371     H         7-dimethylamino                                             1372     H         7-dimethylamino                                             1373     H         7-dimethylamino                                             1374     H         7-dimethylamino                                             1375     H         7-dimethylamino                                             1376     H         7-dimethylamino                                             1377     H         7-dimethylamino                                             1378     H         7-dimethylamino                                             1379     H         7-dimethylamino                                             1380     H         7-dimethylamino                                             1381     H         7-dimethylamino                                             1382     H         7-dimethylamino                                             1383     H         7-dimethylamino                                             1384     H         7-dimethylamino                                             1385     H         7-dimethylamino                                             1386     H         7-dimethylamino                                             1387     H         7-dimethylamino                                             1388     H         7-dimethylamino                                             1389     H         7-dimethylamino                                             1390     H         7-dimethylamino                                             1391     H         7-dimethylamino                                             1392     H         7-dimethylamino                                             1393     H         7-dimethylamino                                             1394     H         7-dimethylamino                                             1395     H         7-dimethylamino                                             1396     H         7-dimethylamino                                             1397     H         7-dimethylamino                                             1398     H         7-dimethylamino                                             1399     H         7-dimethylamino                                             1400     H         7-dimethylamino                                             1401     H         7-dimethylamino                                             1402     H         7-dimethylamino                                             1403     H         7-dimethylamino                                             1404     H         7-dimethylamino                                             1405     H         7-dimethylamino                                             1406     H         7-dimethylamino                                             1407     H         7-dimethylamino                                             1408     H         7-dimethylamino                                             1409     H         7-dimethylamino                                             1410     H         7-dimethylamino                                             1411     H         7-dimethylamino                                             1412     H         7-dimethylamino                                             1413     *H        7-dimethylamino                                             1414     H         7-dimethylamino                                             1415     H         7-dimethylamino                                             1416     H         7-dimethylamino                                             1417     H         7-dimethylamino                                             1418     H         7-dimethylamino                                             1419     H         7-dimethylamino                                             1420     H         7-dimethylamino                                             1421     H         7-dimethylamino                                             1422     H         7-dlmethylamino                                             1423     H         7-dimethylamino                                             1424     H         7-dimethylamino                                             1425     H         7-dimethylamino                                             1426     H         7-dimethylamino                                             1427     H         7-dimethylamino                                             1428     H         7-dimethylamino                                             1429     H         7-dimethylamino                                             1430     H         7-dimethylamino                                             1431     H         7-dimethylamino                                             1432     H         7-dimethylamino                                             1433     H         7-dimethylamino                                             1434     H         7-dimethylamlno                                             1435     H         7-dimethylamino                                             1436     H         7-dimethylamlno                                             1437     H         7-dimethylamino                                             1438     H         7-dimethylamino                                             1439     H         7-dimethylamino                                             1440     H         7-dimethylamino                                             1441     H         7-dimethylamino                                             1442     H         7-dimethylamino                                             1443     H         7-dimethylamino                                             1444     H         7-dimethylamino                                             1445     H         7-dimethylamino                                             1446     H         7-methoxy; 8-methoxy                                        1447     H         7-dimethylamino                                             1448     H         7-dimethylamino                                             1449     H         7-dimethylamino                                             1450     H         7-dimethylamino                                             1451     H         7-dimethylamino                                             __________________________________________________________________________      ##STR309##

PEG=3400 molecular weight polyethylene glycol polymer chain ##STR310##

PEG=3400 molecular weight polyethylene glycol polymer chain ##STR311##

PEG=3400 molecular weight polyethylene glycol polymer chain ##STR312##

In further compounds of the present invention, R⁵ and R⁶ are independently selected from among hydrogen and ring-carbon substituted or unsubstituted aryl, thiophene, pyridine, pyrrole, thiazole, imidazole, pyrazole, pyrimidine, morpholine, N-alkylpyridinium, N-alkylpiperazinium, N-alkylmorpholinium, or furan in which the substituent(s) are selected from among halo, hydroxyl, trihaloalkyl, alkoxy, amino, N-alkylamino, N,N-dialkylamino, quaternary ammonium salts, a C₁ to C₄ alkylene bridge having a quaternary ammonium salt substituted thereon, alkoxycarbonyl, aryloxycarbonyl, alkylcarbonyloxy and arylcarbonyloxy, (O,O)-dioxyalkylene,

--[O(CH₂)_(w) ]_(x) X where x is 2 to 12, w is 2 or 3 and X comprises halo or a quaternary ammonium salt, thiophene, pyridine, pyrrole, thiazole, imidazole, pyrazole, or furan. The aryl group of R⁵ or R⁶ is preferably phenyl, phenylene, or benzene triyl, i.e., may be unsubstituted, mono-substituted, or di-substituted. Among the species which may constitute the substituents on the aryl ring of R⁵ or R⁶ are fluoro, chloro, bromo, methoxy, ethoxy, isopropoxy, trimethylammonium (preferably with an iodide or chloride counterion), methoxycarbonyl, ethoxycarbonyl, formyl, acetyl, propanoyl, (N)-hexyldimethylammonium, hexylenetrimethylammonium, tri(oxyethylene)iodide, and tetra(oxyethylene)trimethyl-ammonium iodide, each substituted at the p-position, the m-position, or both of the aryl ring. Other substituents that can be present on a phenylene, benzene triyl or other aromatic ring include 3,4-dioxymethylene (5-membered ring) and 3,4-dioxyethylene (6-membered ring). Among compounds which have been or can be demonstrated to have desirable ileal bile acid transport inhibiting properties are those in which R⁵ or R⁶ is selected from phenyl, p-fluorophenyl, m-fluorophenyl, p-hydroxyphenyl, m-hydroxyphenyl, p-methoxyphenyl, m-methoxyphenyl, p-N,N-dimethylaminophenyl, m-N,N-dimethylaminophenyl, I⁻ p-(CH₃)₃ --N⁺ -phenyl, I⁻ m-(CH₃)₃ --N⁺ -phenyl, I⁻ m-(CH₃)₃ --N⁺ --CH₂ CH₂ --(OCH₂ CH₂)₂ --O-phenyl, I⁻ p-(CH₃)₃ --N⁺ --CH₂ CH₂ --(OCH₂ CH₂)₂ --O-phenyl, I⁻ m-(N,N-dimethylpiperazinium)-(N')--CH₂ --(OCH₂ CH₂)₂ --O-phenyl, 3-methoxy-4-fluorophenyl, thienyl-2-yl, 5-cholorothienyl-2-yl, 3,4-difluorophenyl, I⁻ p-(N,N-dimethylpiperazinium)-(N')--CH₂ --(OCH₂ CH₂)₂ --O-phenyl, 3-fluoro-4-methoxyphenyl, -4-pyridinyl, 2-pyridinyl, 3-pyridinyl, N-methyl-4-pyridinium, I⁻ N-methyl-3-pyridinium, 3,4-dioxymethylenephenyl, 3,4-dioxyethylenephenyl, and p-methoxycarbonylphenyl. Preferred compounds include 3-ethyl-3-butyl and 3-butyl-3-butyl compounds having each of the above preferred R⁵ substituents in combination with the R^(x) substituents shown in Table 1. It is particularly preferred that one but not both of R⁵ and R⁶ is hydrogen.

It is especially preferred that R⁴ and R⁶ be hydrogen, that R³ and R⁵ not be hydrogen, and that R³ and R⁵ be oriented in the same direction relative to the plane of the molecule, i.e., both in α- or both in β-configuration. It is further preferred that, where R² is butyl and R¹ is ethyl, then R¹ has the same orientation relative to the plane of the molecule as R³ and R⁵.

Set forth in Table 1A are lists of species of R¹ /R², R⁵ /R⁶ and R^(x).

                                      TABLE 1A                                     __________________________________________________________________________     Alternative R Groups                                                            ##STR313##                                                                    R.sup.1, R.sup.2                                                                        R.sup.3, R.sup.4                                                                   R.sup.5        (R.sup.x)q                                         __________________________________________________________________________     ethyl    HO--                                                                               Ph-            7-methyl                                           n-propyl H-- p-F-Ph-        7-ethyl                                            n-butyl      m-F-Ph-        7-iso-propyl                                       n-pentyl     p-CH.sub.3 O-Ph-                                                                              7-tert-butyl                                       n-hexyl      p-CH.sub.3 O-Ph-                                                                              7-OH                                               iso-propyl   m-CH.sub.3 O-Ph-                                                                              7-OCH.sub.3                                        iso-butyl    p-(CH.sub.3).sub.2 N-Ph-                                                                      7-O(iso-propyl)                                    iso-pentyl   m-(CH.sub.3).sub.2 N-Ph-                                                                      7-SCH.sub.3                                        CH.sub.2 C(═O)C.sub.2 H.sub.5                                                           I.sup.-, p-(CH.sub.3).sub.3 --N.sup.+ -Ph-                                                    7-SOCH.sub.3                                       CH.sub.2 OC.sub.2 H.sub.5                                                                   I.sup.-, m-(CH.sub.3).sub.3 --N.sup.+ -Ph-                                                    7-SO.sub.2 CH.sub.3                                CH.sub.2 CH(OH)C.sub.2 H.sub.5                                                              I.sup.-, p-(CH.sub.3).sub.3 --N.sup.+ --CH.sub.2 CH.sub.2                                     7-SCH.sub.2 CH.sub.3                               CH.sub.2 O-(4-picoline)                                                                     (OCH.sub.2 CH.sub.2).sub.2 --O-Ph-                                                            7-NH.sub.2                                                      I.sup.-, m-(CH.sub.3).sub.3 --N.sup.+ --CH.sub.2 CH.sub.2                                     7-NHOH                                                          (OCH.sub.2 CH.sub.2).sub.2 --O-Ph-                                                            7-NHCH.sub.3                                                    I.sup.-, p-(N,N-                                                                              7-N(CH.sub.3).sub.2                                             dimethylpiperazine)-                                                                          7-N.sup.+ (CH.sub.3).sub.3, I.sup.-                             (N')-CH.sub.2 -(OCH.sub.2 CH.sub.2).sub.2 --O-Ph-                                             7-NHC(═O)CH.sub.3                                                          7-N(CH.sub.2 CH.sub.3).sub.2                                    I.sup.-, m-(N,N-                                                                              7-NMeCH.sub.2 CO.sub.2 H                                        dimethylpiperazine)-                                                                          7-N.sup.+ (Me).sub.2 CH.sub.2 CO.sub.2 H,                                      I.sup.-                                                         (N')-CH.sub.2 -(OCH.sub.2 CH.sub.2).sub.2 --O-Ph-                                             7-(N)-morpholine                                                m-F, p-CH.sub.3 O-Ph-                                                                         7-(N)-azetidine                                                 3,4,dioxymethylene-Ph                                                                         7-(N)-N-methylazetidinium, I.sup.-                              m-CH.sub.3 O--, p-F-Ph-                                                                       7-(N)-pyrrolidine                                               4-pyridine     7-(N)-N-methyl-                                                 N-methyl-4-pyridinium, I.sup.-                                                                pyrrolidinium, I.sup.-                                          3-pyridine     7-(N)-N-methyl-                                                 N-methyl-3-pyridinium, I.sup.-                                                                morpholinium, I.sup.-                                           2-pyridine     7-(N)-N'-methylpiperazine                                       p-CH.sub.3 O.sub.2 C-Ph-                                                                      7-(N)-N'-                                                       thienyl-2-yl   dimethylpiperazinium, I.sup.-                                   5-Cl-thienyl-2-yl                                                                             7-NH-CBZ                                                                       7-NHC(O)C.sub.5 H.sub.11                                                       7-NHC(O)CH.sub.2 Br                                                            7-NH--C(NH)NH.sub.2                                                            7-(2)-thiophene                                                                8-methyl                                                                       8-ethyl                                                                        8-iso-propyl                                                                   8-tert-butyl                                                                   8-OH                                                                           8-OCH.sub.3                                                                    8-O(iso-propyl)                                                                8-SCH.sub.3                                                                    8-SOCH.sub.3                                                                   8-SO.sub.2 CH.sub.3                                                            8-SCH.sub.2 CH.sub.3                                                           8-NH.sub.2                                                                     8-NHOH                                                                         8-NHCH.sub.3                                                                   8-N(CH.sub.3).sub.2                                                            8-N.sup.+ (CH.sub.3).sub.3, I.sup.-                                            8-NHC(═O)CH.sub.3                                                          8-N(CH.sub.2 CH.sub.3).sub.2                                                   8-NMeCH.sub.2 CO.sub.2 H                                                       8-N.sup.+ (Me).sub.2 CH.sub.2 CO.sub.2 H,                                      I.sup.-                                                                        8-(N)-morpholine                                                               8-(N)-azetidine                                                                8-(N)-N-methylazetidinium, I.sup.-                                             8-(N)-pyrrolidine                                                              8-(N)-N-methylpyrrolidinium, I.sup.-                                           8-(N)-N-methylmorpholinium, I.sup.-                                            8-(N)-N'-methylpiperazine                                                      8-(N)-N'-dimethylpiperazinium, I.sup.-                                         8-NH--CBZ                                                                      8-NHC(O)C.sub.5 H.sub.11                                                       8-NHC(O)CH.sub.2 Br                                                            8-NH--C(NH)NH.sub.2                                                            8-(2)-thiophene                                                                9-methyl                                                                       9-ethyl                                                                        9-iso-propyl                                                                   9-tert-butyl                                                                   9-OH                                                                           9-OCH.sub.3                                                                    9-O(iso-propyl)                                                                9-SCH.sub.3                                                                    9-SOCH.sub.3                                                                   9-SO.sub.2 CH.sub.3                                                            9-SCH.sub.2 CH.sub.3                                                           9-NH.sub.2                                                                     9-NHOH                                                                         9-NHCH.sub.3                                                                   9-N(CH.sub.3).sub.2                                                            9-N.sup.+ (CH.sub.3).sub.3, I.sup.-                                            9-NHC(═O)CH.sub.3                                                          9-N(CH.sub.2 CH.sub.3).sub.2                                                   9-NMeCH.sub.2 CO.sub.2 H                                                       9-N.sup.+ (Me).sub.2 CH.sub.2 CO.sub.2 H,                                      I.sup.-                                                                        9-(N)-morpholine                                                               9-(N)-azetidine                                                                9-(N)-N-methylazetidinium, I.sup.-                                             9-(N)-pyrrolidine                                                              9-(N)-N-methylpyrrolidinium, I.sup.-                                           9-(N)-N-methylmorpholinium, I.sup.-                                            9-(N)-N'-methylpiperazine                                                      9-(N)-N'-dimethylpiperazinium, I.sup.-                                         9-NH--CBZ                                                                      9-NHC(O)C.sub.5 H.sub.11                                                       9-NHC(O)CH.sub.2 Br                                                            9-NH--C(NH)NH.sub.2                                                            9-(2)-thiophene                                                                7-OCH.sub.3, 8-OCH.sub.3                                                       7-SCH.sub.3, 8-OCH.sub.3                                                       7-SCH.sub.3, 8-SCH.sub.3                                                       6-OCH.sub.3, 7-OCH.sub.3, 8-OCH.sub.3              __________________________________________________________________________

Further preferred compounds of the present invention comprise a core structure having two or more pharmaceutically active benzothiepine structures as described above, covalently bonded to the core moiety via functional linkages. Such active benzothiepine structures preferably comprise: ##STR314## where R¹, R², R³, R⁴, R⁶, R⁵, R⁶, R⁷, R⁸, X, q and n are as defined above, and R⁵⁵ is either a covalent bond or arylene.

The core moiety can comprise alkane diyl, alkene diyl, alkyne diyl, polyalkane diyl, alkoxy diyl, polyether diyl, polyalkoxy diyl, carbohydrate, amino acid, and peptide, polypeptide, wherein alkane diyl, alkene diyl, alkyne diyl, polyalkane diyl, alkoxy diyl, polyether diyl, polyalkoxy diyl, carbohydrate, amino acid, and peptide polypeptide, can optionally have one or more carbon replaced by O, NR⁷, N⁺ R⁷ R⁸, S, SO, SO2, S⁺ R⁷ R⁸, PR7, P+R7R8, phenylene, heterocycle, quatarnary heterocycle, quaternary heteroaryl, or aryl,

wherein alkane diyl, alkene diyl, alkyne diyl, polyalkane diyl, alkoxy diyl, polyether diyl, polyalkoxy diyl, carbohydrate, amino acid, peptide, and polypeptide can be substituted with one or more substituent groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle, arylalkyl, halogen, oxo, OR¹³, NR¹³ R¹⁴, SR¹³, S(O)R¹³, SO₂ R¹³, SO₃ R¹³, NR¹³ OR¹⁴, NR¹³ NR¹⁴ R¹⁵, NO₂, CO₂ R¹³, CN, OM, SO₂ OM, SO₂ NR¹³ R¹⁴, C(O)NR¹³ R¹⁴, C(O)OM, COR¹³, P(O)R¹³ R¹⁴, P⁺ R¹³ R¹⁴ R15A-, P(OR¹³)OR¹⁴, S⁺ R¹³ R¹⁴ A⁻, and N⁺ R⁹ R¹¹ R¹² A⁻ ;

wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, and heterocycle can be further substituted with one or more substituent groups selected from the group consisting of OR⁷, NR⁷ R⁸, SR⁷, S(O)R⁷, SO₂ R⁷, SO₃ R⁷, CO₂ R⁷, CN, oxo, CONR⁷ R⁸, N⁺ R⁷ R⁸ R⁹ A-, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, arylalkyl, quaternary heterocycle, quaternary heteroaryl, P(O)R⁷ R⁸, P⁺ R⁷ R⁸ A⁻, and P(O)(OR⁷)OR⁸, and

wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, and heterocycle can optionally have one or more carbons replaced by O, NR⁷, N⁺ R⁷ R⁸ A-, S, SO, SO₂, S⁺ R⁷ A-, PR⁷, P(O)R⁷, P⁺ R⁷ R⁸ A-, or phenylene.

Exemplary core moieties include: ##STR315## wherein: R²⁵ is selected from the group consisting of C and N, and

R²⁶ and R²⁷ are independently selected from the group consisting of: ##STR316## wherein R²⁶, R²⁹, R³⁰ and R³¹ are independently selected from alkyl, alkenyl, alkylaryl, aryl, arylalkyl, cycloalkyl, heterocycle, and heterocycloalkyl,

A⁻ is a pharmaceutically acceptable anion, and k=1 to 10.

In compounds of Formula DIV, R²⁰, R²¹, R²² in Formulae DII and DIII, and R²³ in Formula DIII can be bonded at any of their 6-, 7-, 8-, or 9-positions to R¹⁹. In compounds of Formula DIVA, it is preferred that R⁵⁵ comprises a phenylene moiety bonded at a m- or p-position thereof to R¹⁹.

In another embodiment, a core moiety backbone, R¹⁹, as discussed herein in Formulas DII and DIII can be multiply substituted with more than four pendant active benzothiepine units, i.e., R²⁰, R²¹, R²², and R²³ as discussed above, through multiple functional groups within the core moiety backbone. The core moiety backbone unit, R¹⁹, can comprise a single core moiety unit, multimers thereof, and multimeric mixtures of the different core moiety units discussed herein, i.e., alone or in combination. The number of individual core moiety backbone units can range from about one to about 100, preferably about one to about 80, more preferably about one to about 50, and even more preferably about one to about 25. The number of points of attachment of similar or different pendant active benzothiepine units within a single core moiety backbone unit can be in the range from about one to about 100, preferably about one to about 80, more preferably about one to about 50, and even more preferably about one to about 25. Such points of attachment can include bonds to C, S, O, N, or P within any of the groups encompassed by the definition of R¹⁹.

The more preferred benzothiepine moieties comprising R²⁰, R²¹, R²² and/or R²³ conform to the preferred structures as outlined above for Formula I. The 3-carbon on each benzothiepine moiety can be achiral, and the substituents R¹, R², R³, R⁴, R⁵ and R^(x) can be selected from the preferred groups and combinations of substituents as discussed above. The core structures can comprise, for example, poly(exyalkylene) or oligo(oxyalkylene), especially poly- or oligo(exyethylene) or poly- or oligo(oxypropylene).

Dosages, Formulations, and Routes of Administration

The ileal bile acid transport inhibitor compounds of the present invention can be administered for the prophylaxis and treatment of hyperlipidemic diseases or conditions by any means, preferably oral, that produce contact of these compounds with their site of action in the body, for example in the ileum of a mammal, e.g., a human.

For the prophylaxis or treatment of the conditions referred to above, the compounds of the present invention can be used as the compound per se.

Pharmaceutically acceptable salts are particularly suitable for medical applications because of their greater aqueous solubility relative to the parent compound. Such salts must clearly have a pharmaceutically acceptable anion or cation. Suitable pharmaceutically acceptable acid addition salts of the compounds of the present invention when possible include those derived from inorganic acids, such as hydrochloric, hydrobromic, phosphoric, metaphosphoric, nitric, sulfonic, and sulfuric acids, and organic acids such as acetic, benzenesulfonic, benzoic, citric, ethanesulfonic, fumaric, gluconic, glycolic, isothionic, lactic, lactobionic, maleic, malic, methanesulfonic, succinic, toluenesulfonic, tartaric, and trifluoroacetic acids. The chloride salt is particularly preferred for medical purposes. Suitable pharmaceutically acceptable base salts include ammonium salts, alkali metal salts such as sodium and potassium salts, and alkaline earth salts such as magnesium and calcium salts.

The anions of the definition of A⁻ in the present invention are, of course, also required to be pharmaceutically acceptable and are also selected from the above list.

The compounds of the present invention can be presented with an acceptable carrier in the form of a pharmaceutical composition. The carrier must, of course, be acceptable in the sense of being compatible with the other ingredients of the composition and must not be deleterious to the recipient. The carrier can be a solid or a liquid, or both, and is preferably formulated with the compound as a unit-dose composition, for example, a tablet, which can contain from 0.05% to 95% by weight of the active compound. Other pharmacologically active substances can also be present, including other compounds of the present invention. The pharmaceutical compositions of the invention can be prepared by any of the well known techniques of pharmacy, consisting essentially of admixing the components.

These compounds can be administered by any conventional means available for use in conjunction with pharmaceuticals, either as individual therapeutic compounds or as a combination of therapeutic compounds.

The amount of compound which is required to achieve the desired biological effect will, of course, depend on a number of factors such as the specific compound chosen, the use for which it is intended, the mode of administration, and the clinical condition of the recipient.

In general, a daily dose can be in the range of from about 0.3 to about 100 mg/kg bodyweight/day, preferably from about 1 mg to about 50 mg/kg bodyweight/day, more preferably from about 3 to about 10 mg/kg bodyweight/day. This total daily dose can be administered to the patient in a single dose, or in proportionate multiple subdoses. Subdoses can be administered 2 to 6 times per day. Doses can be in sustained release form effective to obtain desired results.

Orally administrable unit dose formulations, such as tablets or capsules, can contain, for example, from about 0.1 to about 100 mg of benzothiepine compound, preferably about 1 to about 75 mg of compound, more preferably from about 10 to about 50 mg of compound. In the case of pharmaceutically acceptable salts, the weights indicated above refer to the weight of the benzothiepine ion derived from the salt.

Oral delivery of an ileal bile acid transport inhibitor of the present invention can include formulations, as are well known in the art, to provide prolonged or sustained delivery of the drug to the gastrointestinal tract by any number of mechanisms. These include, but are not limited to, pH sensitive release from the dosage form based on the changing pH of the small intestine, slow erosion of a tablet or capsule, retention in the stomach based on the physical properties of the formulation, bioadhesion of the dosage form to the mucosal lining of the intestinal tract, or enzymatic release of the active drug from the dosage form. The intended effect is to extend the time period over which the active drug molecule is delivered to the site of action (the ileum) by manipulation of the dosage form. Thus, enteric-coated and enteric-coated controlled release formulations are within the scope of the present invention. Suitable enteric coatings include cellulose acetate phthalate, polyvinylacetate phthalate, hydroxypropylmethylcellulose phthalate and anionic polymers of methacrylic acid and methacrylic acid methyl ester.

When administered intravenously, the dose can, for example, be in the range of from about 0.1 mg/kg body weight to about 1.0 mg/kg body weight, preferably from about 0.25 mg/kg body weight to about 0.75 mg/kg body weight, more preferably from about 0.4 mg/kg body weight to about 0.6 mg/kg body weight. This dose can be conveniently administered as an infusion of from about 10 ng/kg body weight to about 100 ng/kg body weight per minute. Infusion fluids suitable for this purpose can contain, for example, from about 0.1 ng to about 10 mg, preferably from about 1 ng to about 10 mg per milliliter. Unit doses can contain, for example, from about 1 mg to about 10 g of the compound of the present invention. Thus, ampoules for injection can contain, for example, from about 1 mg to about 100 mg.

Pharmaceutical compositions according to the present invention include those suitable for oral, rectal, topical, buccal (e.g., sublingual), and parenteral (e.g., subcutaneous, intramuscular, intradermal, or intravenous) administration, although the most suitable route in any given case will depend on the nature and severity of the condition being treated and on the nature of the particular compound which is being used. In most cases, the preferred route of administration is oral.

Pharmaceutical compositions suitable for oral administration can be presented in discrete units, such as capsules, cachets, lozenges, or tablets, each containing a predetermined amount of at least one compound of the present invention; as a powder or granules; as a solution or a suspension in an aqueous or non-aqueous liquid; or as an oil-in-water or water-in-oil emulsion. As indicated, such compositions can be prepared by any suitable method of pharmacy which includes the step of bringing into association the active compound(s) and the carrier (which can constitute one or more accessory ingredients). In general, the compositions are prepared by uniformly and intimately admixing the active compound with a liquid or finely divided solid carrier, or both, and then, if necessary, shaping the product. For example, a tablet can be prepared by compressing or molding a powder or granules of the compound, optionally with one or more assessory ingredients. Compressed tablets can be prepared by compressing, in a suitable machine, the compound in a free-flowing form, such as a powder or granules optionally mixed with a binder, lubricant, inert diluent and/or surface active/dispersing agent(s). Molded tablets can be made by molding, in a suitable machine, the powdered compound moistened with an inert liquid diluent.

Pharmaceutical compositions suitable for buccal (sub-lingual) administration include lozenges comprising a compound of the present invention in a flavored base, usually sucrose, and acacia or traqacanth, and pastilles comprising the compound in an inert base such as gelatin and glycerin or sucrose and acacia.

Pharmaceutical compositions suitable for parenteral administration conveniently comprise sterile aqueous preparations of a compound of the present invention. These preparations are preferably administered intravenously, although administration can also be effected by means of subcutaneous, intramuscular, or intradermal injection. Such preparations can conveniently be prepared by admixing the compound with water and rendering the resulting solution sterile and isotonic with the blood. Injectable compositions according to the invention will generally contain from 0.1 to 5% w/w of a compound disclosed herein.

Pharmaceutical compositions suitable for rectal administration are preferably presented as unit-dose suppositories. These can be prepared by admixing a compound of the present invention with one or more conventional solid carriers, for example, cocoa butter, and then shaping the resulting mixture.

Pharmaceutical compositions suitable for topical application to the skin preferably take the form of an ointment, cream, lotion, paste, gel, spray, aerosol, or oil. Carriers which can be used include vaseline, lanoline, polyethylene glycols, alcohols, and combinations of two or more thereof. The active compound is generally present at a concentration of from 0.1 to 15% w/w of the composition, for example, from 0.5 to 2%.

Transdermal administration is also possible. Pharmaceutical compositions suitable for transdermal administration can be presented as discrete patches adapted to remain in intimate contact with the epidermis of the recipient for a prolonged period of time. Such patches suitably contain a compound of the present invention in an optionally buffered, aqueous solution, dissolved and/or dispersed in an adhesive, or dispersed in a polymer. A suitable concentration of the active compound is about 1% to 35%, preferably about 3% to 15%. As one particular possibility, the compound can be delivered from the patch by electrotransport or iontophoresis, for example, as described in Pharmaceutical Research, 3(6), 318 (1986).

In any case, the amount of active ingredient that can be combined with carrier materials to produce a single dosage form to be administered will vary depending upon the host treated and the particular mode of administration.

The solid dosage forms for oral administration including capsules, tablets, pills, powders, and granules noted above comprise one or more compounds of the present invention admixed with at least one inert diluent such as sucrose, lactose, or starch. Such dosage forms may also comprise, as in normal practice, additional substances other than inert diluents, e.g., lubricating agents such as magnesium stearate. In the case of capsules, tablets, and pills, the dosage forms may also comprise buffering agents. Tablets and pills can additionally be prepared with enteric coatings.

Liquid dosage forms for oral administration can include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs containing inert diluents commonly used in the art, such as water. Such compositions may also comprise adjuvants, such as wetting agents, emulsifying and suspending agents, and sweetening, flavoring, and perfuming agents.

Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or setting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.

Pharmaceutically acceptable carriers encompass all the foregoing and the like.

Treatment Regimen

The dosage regimen to prevent, give relief from, or ameliorate a disease condition having hyperlipemia as an element of the disease, e.g., atherosclerosis, or to protect against or treat further high cholesterol plasma or blood levels with the compounds and/or compositions of the present invention is selected in accordance with a variety of factors. These include the type, age, weight, sex, diet, and medical condition of the patient, the severity of the disease, the route of administration, pharmacological considerations such as the activity, efficacy, pharmacokinetics and toxicology profiles of the particular compound employed, whether a drug delivery system is utilized, and whether the compound is administered as part of a drug combination. Thus, the dosage regimen actually employed may vary widely and therefore deviate from the preferred dosage regimen set forth above.

Initial treatment of a patient suffering from a hyperlipidemic condition can begin with the dosages indicated above. Treatment should generally be continued as necessary over a period of several weeks to several months or years until the hyperlipidemic disease condition has been controlled or eliminated. Patients undergoing treatment with the compounds or compositions disclosed herein can be routinely monitored by, for example, measuring serum cholesterol levels by any of the methods well known in the art, to determine the effectiveness of therapy. Continuous analysis of such data permits modification of the treatment regimen during therapy so that optimal effective amounts of compounds of the present invention are administered at any point in time, and so that the duration of treatment can be determined as well. In this way, the treatment regimen/dosing schedule can be rationally modified over the course of therapy so that the lowest amount of ileal bile acid transport inhibitor of the present invention which exhibits satisfactory effectiveness is administered, and so that administration is continued only so long as is necessary to successfully treat the hyperlipidemic condition.

The following non-limiting examples serve to illustrate various aspects of the present invention.

EXAMPLES OF SYNTHETIC PROCEDURES

Preparation 1

2-Ethyl-2-(mesyloxymethyl)hexanal (1) ##STR317##

To a cold (10° C.) solution of 12.6 g (0.11 mole) of methanesulfonyl chloride and 10.3 g (0.13 mole) of triethylamine was added dropwise 15.8 g of 2-ethyl-2-(hydroxymethyl)hexanal, prepared according to the procedure described in Chem. Ber. 98, 728-734 (1965), while maintaining the reaction temperature below 30° C. The reaction mixture was stirred at room temperature for 18 h, quenched with dilute HCl and extracted with methlyene chloride. The methylene chloride extract was dried over MgSO₄ and concentrated in vacuo to give 24.4 g of brown oil.

Preparation 2

2-((2-Benzoylphenylthio)methyl)-2-ethylhexanal (2) ##STR318##

A mixture of 31 g (0.144 mol) of 2-mercaptobenzophenone, prepared according to the procedure described in WO 93/16055, 24.4 g (0.1 mole) of 2-ethyl-2-(mesyloxymethyl)-hexanal (1), 14.8 g (0.146 mole) of triethylamine, and 80 mL of 2-methoxyethyl ether was held at reflux for 24 h. The reaction mixture was poured into 3N HCl and extracted with 300 mL of methylene chloride. The methylene chloride layer was washed with 300 mL of 10% NaOH, dried over MgSO₄ and concentrated in vacuo to remove 2-methoxyethyl ether. The residue was purified by HPLC (10% EtOAc-hexane) to give 20.5 g (58%) of 2 as an oil.

Example 1 3-Butyl-3-ethyl-5-phenyl-2,3-dihydrobenzothiepine (3), cis-3-Butyl-3-ethyl-5-phenyl-2,3-dihydrobenzothiepin-(5H)4-one (4a) and trans-3-Butyl-3-ethyl-5-phenyl-2,3-dihydro-benzothiepin-(5H)4-one (4b) ##STR319##

A mixture of 2.6 g (0.04 mole) of zinc dust, 7.2 g (0.047 mole) of TiCl₃ and 80 mL of anhydrous ethylene glycol dimethyl ether (DME) was held at reflux for 2 h. The reaction mixture was cooled to 5° C. To the reaction mixture was added dropwise a solution of 3.54 g (0.01 mole) of 2 in 30 mL of DME in 40 min. The reaction mixture was stirred at room temperature for 16 h and then was held at reflux for 2 h and cooled before being poured into brine. The organic was extract into methylene chloride. The methylene chloride extract was dried over MgSO₄ and concentrated in vacuo. The residue was purified by HPLC (hexane) to give 1.7 g (43%) of 3 as an oil in the first fraction. The second fraction was discarded and the third fraction was further purified by HPLC (hexane) to give 0.07 g (2%) of 4a in the earlier fraction and 0.1 g (3%) of 4b in the later fraction.

Example 2 cis-3-Butyl-3-ethyl-5-phenyl-2,3-dihydrobenzothiepin-(5H)4-one-1,1-dioxide (5a) and trans-3-Butyl-3-ethyl-5-phenyl-2,3-dihydro-benzothiepin-(5H)4-one-1,1-dioxide (5b) ##STR320##

To a solution of 1.2 g (3.5 mmole) of 50-60% MCPBA in 20 mL of methylene chloride was added 0.59 g (1.75 mmole) of a mixture of 4a and 4b in 10 mL of methylene chloride. The reaction mixture was stirred for 20 h. An additional 1.2 g (1.75 mmole) of 50-60% MAPBA was added and the reaction mixture was stirred for an additional 3 h then was triturated with 50 mL of 10% NaOH. The insoluble solid was filtered. The methylene chloride layer of the filtrate was washed with brine, dried over MgSO₄, and concentrated in vacuo. The residual syrup was purified by HPLC (5% EtOAc-hexane) to give 0.2 g (30%) of 5a as an oil in the first fraction and 0.17 g (26%) of 5b as an oil in the second fraction.

Example 3 (3α,4α,5β) 3-Butyl-3-ethyl-4-hydroxy-5-phenyl-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (6a), (3α,4β,5α) 3-Butyl-3-ethyl-4-hydroxy-5-phenyl-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (6b), (3α,4α,5α) 3-Butyl-3-ethyl-4-hydroxy-5-phenyl-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (6c), and (3α,4β,5β) 3-Butyl-3-ethyl-4-hydroxy-5-phenyl-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (6d) ##STR321## A. Reduction of 5a and 5b with Sodium Borohydride

To a solution of 0.22 g (0.59 mmole) of 5b in 10 mL of ethanol was added 0.24 g (6.4 mmole) of sodium borohydride. The reaction mixture was stirred at room temperature for 18 h and concentrated in vacuo to remove ethanol. The residue was triturated with water and extracted with methylene chloride. The methylene chloride extract was dried over MgSO₄ and concentrated in vacuo to give 0.2 g of syrup. In a separate experiment, 0.45 g of 5a was treated with 0.44 g of sodium borohydride in 10 mL of ethanol and was worked up as described above to give 0.5 g of syrup which was identical to the 0.2 g of syrup obtained above. These two materials were combined and purified by HPLC using 10% EtOAc-hexane as eluant. The first fraction was 0.18 g (27%) of 6a as a syrup. The second fraction was 0.2 g (30%) of 6b also as a syrup. The column was then eluted with 20% EtOAc-hexane to give 0.077 g (11%) of 6c in the third fraction as a solid. Recrystallization from hexane gave a solid, mp 179-181° C. Finally, the column was eluted with 30% EtOAc-hexane to give 0.08 g (12%) of 6d in the fourth fraction as a solid. Recrystallization from hexane gave a solid, mp 160-161° C.

B. Conversion of 6a to 6c and 6d with NaOH and PTC

To a solution of 0.29 g (0.78 mmole) of 6a in 10 mL CH₂ Cl₂, was added 9 g of 40% NaOH. The reaction mixture was stirred for 0.5 h at room temperature and was added one drop of Aliquat-336 (methyltricaprylylammonium chloride) phase transfer catalyst (PTC). The mixture was stirred for 0.5 h at room temperature before being treated with 25 mL of ice-crystals then was extracted with CH₂ Cl₂ (3×10 ml), dried over MgSO₄ and concentrated in vacuo to recover 0.17 g of a colorless film. The components of this mixture were separated using an HPLC and eluted with EtOAc-hexane to give 12.8 mg (4%) of 2-(2-benzylphenylsulfonylmethyl)-2-ethylhexenal in the first fraction, 30.9 mg (11%) of 6c in the second fraction and 90.0 mg (31%) of 6d in the third fraction.

Oxidation of 6a to 5b

To a solution of 0.20 g (0.52 mmole) of 6a in 5 mL of CH₂ Cl₂ was added 0.23 g (1.0 mmole) of pyridinium chlorochromate. The reaction mixture was stirred for 2 h then was treated with additional 0.23 g of pyridinium chlorochromate and stirred overnight. The dark reaction mixture was poured into a ceramic filterfrit containing silica gel and was eluted with CH₂ Cl₂. The filtrate was concentrated in vacuo to recover 167 mg (87%) of 5b as a colorless oil.

Example 4 3-Butyl-3-ethyl-5-phenyl-2,3-dihydrobenzothiepine-1,1-dioxide (7) ##STR322##

To a solution of 5.13 g (15.9 mmole) of 3 in 50 mL of CH₂ Cl₂ was added 10 g (31.9 mmole) of 50-60% MCPBA (m-chloroperoxybenzoic acid) portionwise causing a mild reflux and formation of a white solid. The reaction mixture was allowed to stir overnight under N₂ and was triturated with 25 mL of water followed by 50 mL of 10% NaOH solution. The organic was extracted into CH₂ Cl₂ (4×20 mL). The CH₂ Cl₂ extract was dried over MgSO₄ and evaporated to dryness to recover 4.9 g (87%) of an opaque viscous oil.

Example 5 (1aα,2β,8bα) 2-Butyl-2-ethyl-8b-phenyl-1α,2,3,8b-tetrahydro-benzothiepino[4,5-b]oxirene-4,4-dioxide (8a) (1aα,2α,8bα) 2-Butyl-2-ethyl-8b-phenyl-1a,2,3,8b-tetrahydro-benzothiepino[4,5-b]oxirene-4,4-dioxide (8b) ##STR323##

To 1.3 g (4.03 mole) of 3 in 25 mL of CHCl₃ was added portionwise 5 g (14.1 mmole) of 50-60% MCPBA causing a mild exotherm. The reaction mixture was stirred under N₂ overnight and was then held at reflux for 3 h. The insoluble white slurry was filtered. The filtrate was extracted with 10% potassium carbonate (3×50 mL), once with brine, dried over MgSO₄, and concentrated in vacuo to give 1.37 g of a light yellow oil. Purification by HPLC gave 0.65 g of crystalline product. This product is a mixture of two isomers. Trituration of this crystalline product in hexane recovered 141.7 mg (10%) of a white crystalline product. This isomer was characterized by NMR and mass spectra to be the 1aα,2β,8bα) isomer 8a. The hexane filtrate was concentrated in vacuo to give 206 mg of white film which is a mixture of 30% 8a and 70% 8b by ¹ H NMR.

Example 6 cis-3-Butyl-3-ethyl-5-phenyl-2,3,4,5-tetrahydro-benzothiepine-1,1-dioxide (9a), trans-3-Butyl-3-ethyl-5-phenyl-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (9b), and 3-Butyl-3-ethyl-4-hydroxy-5-cyclohexylidine-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (10) ##STR324##

A mixture of 0.15 g (0.4 mmole) of a 3:7 mixture of 8a and 8b was dissolved in 15 ml MeOH in a 3 oz. Fisher/Porter vessel, then was added 0.1 g of 10% Pd/C catalyst. This mixture was hydrogenated at 70 psi H₂ for 5 h and filtered. The filtrate was evaporated to dryness in vacuo to recover 0.117 g of a colorless oil. This material was purified by HPLC eluting with EtOAc-hexane. The first fraction was 4.2 mg (3%) of 9b. The second fraction, 5.0 mg (4%), was a 50/50 mixture of 9a and 9b. The third fraction was 8.8 mg (6%) of 6a. The fourth fraction was 25.5 mg (18%) of 6b. The fifth fraction was 9.6 mg (7%) of a mixture of 6b and a product believed to be 3-butyl-3-ethyl-4,5-dihydroxy-5-phenyl-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide based on mass spectrum. The sixth fraction was 7.5 mg (5%) of a mixture of 6d and one of the isomers of 10, 10a.

Example 7

In another experiment, a product (3.7 g) from epoxidation of 3 with excess MCPBA in refluxing CHCl₃ under air was hydrogenated in 100 mL of methanol using 1 g of 10% Pd/C catalyst and 70 psi hydrogen. The product was purified by HPLC to give 0.9 g (25%) of 9b, 0.45 g (13%) of 9a, 0.27 g (7%) of 6a, 0.51 g (14%) of 6b, 0.02 g (1%) of 6c, 0.06 g (2%) of one isomer of 10, 10a and 0.03 g (1%) of another isomer of 10, 10b.

Example 8 2-((2-Benzoylphenylthio)methyl)butyraldehyde (11) ##STR325##

To an ice bath cooled solution of 9.76 g (0.116 mole) of 2-ethylacrolein in 40 mL of dry THF was added 24.6 g (0.116 mole) of 2-mercaptobenzophenone in 40 mL of THF followed by 13 g (0.128 mole) of triethylamine. The reaction mixture was stirred at room temperature for 3 days, diluted with ether, and was washed successively with dilute HCl, brine, and 1 M potassium carbonate. The ether layer was dried over MgSO₄ and concentrated in vacuo. The residue was purified by HPLC (10% EtOAc-hexane) to give 22 g (64%) of 11 in the second fraction. An attempt to further purifiy this material by kugelrohr distillation at 0.5 torr (160-190° C.) gave a fraction (12.2 g) which contained starting material indicating a reversed reaction during distillation. This material was dissolved in ether (100 mL) and was washed with 50 mL of 1 M potassium carbonate three times to give 6.0 g of a syrup which was purified by HPLC (10% EtOAc-hexane) to give 5.6 g of pure 11.

Example 9 3-Ethyl-5-phenyl-2,3-dihydrobenzothiepine (12) ##STR326##

To a mixture of 2.61 g (0.04 mole) of zinc dust and 60 mL of DME was added 7.5 g (0.048 mole) of TiCl₃. The reaction mixture was held at reflux for 2 h. A solution of 2.98 g (0.01 mole) of 11 was added dropwise in 1 h. The reaction mixture was held at reflux for 18 h, cooled and poured into water. The organic was extracted into ether. The ether layer was washed with brine and filtered through Celite. The filtrate was dried over MgSO₄ and concentrated. The residual oil (2.5 g) was purified by HPLC to give 2.06 g (77%) of 12 as an oil in the second fraction.

Example 10 1aα,2α,8bα) 2-Ethyl-8b-phenyl-1a,2,3,8b-tetrahydro-benzothiepino-[4,5-b]oxirene-4,4-dioxide (13) ##STR327##

To a solution of 1.5 g (5.64 mmole) of 12 in 25 ml of CHCl₃ was added 6.8 g (19.4 mmole) of 50-60% MCPB portionwise causing an exothem and formation of a white solid. The mixture was stirred at room temperature overnight diluted with 100 ml methylene chloride and washed successively with 10% K₂ CO₃ (4×50 ml), water (twice with 25 ml) and brine. The organic layer was then dried over MgSO₄ and evaporated to dryness to recover 1.47 g of an off white solid. ¹ H NMR indicated that only one isomer is present. This solid was slurried in 200 ml of warm Et₂ O and filtered to give 0.82 g (46%) of 13 as a white solid, mp 185-186.5° C.

Example 11 (3α,4β,5α)-3-Ethyl-4-hydroxy-5-phenyl-2,3,4,5-tetrahydro-benzothiepine-1,1-dioxide (14a), (3α,4β,5β) 3-Ethyl-4-hydroxy-5-phenyl-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (14b), and cis-3-Ethyl-5-phenyl-2,3,4,5-tetrahydro-benzothiepine-1,1-dioxide (15) ##STR328##

A mixture of 0.5 g (1.6 mole) of 13, 50 ml of acetic acid and 0.5 g of 10% Pd/C catalyst was hydrogenated with 70 psi hydrogen for 4 h. The crude reaction slurry was filtered and the filtrate was stirred with 150 ml of a saturated NaHCO₃ solution followed by 89 g of NaHCO₃ powder portionwise to neutralize the rest of acetic acid. The mixture was extracted with methylene chloride (4×25 ml), then the organic layer was dried over MgSO₄ and concentrated in vacuo to give 0.44 g (87%) of a voluminous white solid which was purified by HPLC (EtOAc-Hexane) to give 26.8 mg (6%) of 15 in the first fraction, 272 mg (54%) of 14a as a solid, mp 142-143.5° C., in the second fraction, and 35 mg (7%) of impure 14b in the third fraction.

Example 12 2-Ethyl-2-((2-Hydroxymethylphenyl)thiomethyl)hexenal (16) ##STR329##

A mixture of 5.0 g (0.036 mole) of 2-mercaptobenzyl alcohol, 6.4 g (0.032 mole) of 1, 3.6 g (0.036 mole) of triethylamine and 25 mL of 2-methoxyethyl ether was held at reflux for 7 h. Additional 1.1 g of mercaptobenzyl alcohol and 0.72 g of triethylamine was added to the reaction mixture and the mixture was held at reflux for additional 16 h. The reaction mixture was cooled and poured into 6N HCl and extracted with methylene chloride. The methylene chloride extract was washed twice with 10% NaOH, dried over MgSO₄ and concentrated in vacuo to give 9.6 g of residue. Purification by HPLC (20% EtOAc-hexane) gave 3.7 g (41%) of 16 as an oil.

Example 13 2-Ethyl-2-((2-formylphenyl)thiomethyl)hexenal (17) ##STR330##

A mixture of 3.7 g of 16, 5.6 g (0.026 mole) of pyridinium chlorochromate, 2 g of Celite and 30 mL of methylene chloride was stirred for 18 h and filtered through a bed of silica gel. The silica gel was eluted with methylene chloride. The combined methylene chloride eluant was purified by HPLC (20% ETOAc-hexane) to give 2.4 g (66%) of an oil.

Example 14 3-Butyl-3-ethyl-2,3-dihydrobenzothiepine (18) ##STR331##

A mixture of 2.6 g (0.04 mole) of zinc dust, 7.2 g (0.047 mole) of TiCl₃, and 50 mL of DME was held at reflux for 2 h and cooled to room temperature. To this mixture was added 2.4 g (8.6 mmole) of 17 in 20 mL of DME in 10 min. The reaction mixture was stirred at room temperature for 2 h and held at reflux for 1 h then was let standing at room temperature over weekend. The reaction mixture was poured into dilute HCl and was stirred with methylene chloride. The methylene chloride-water mixture was filtered through Celite. The methylene chloride layer was washed with brine, dried over MgSO₄, and concentrated in vacuo to give 3.0 g of a residue. Purification by HPLC gave 0.41 g (20%) of 18 as an oil in the early fraction.

Example 15 (1aα,2α,8bα) 2-Butyl-2-ethyl-1a,2,3,8b-tetrahydro-benzothiepino[4,5-b]oxirene-4,4-dioxide (19a) and (1aα,2β,8bα) 2-Butyl-2-ethyl-8b-phenyl-1a,2,3,8b-tetrahydro-benzothiepino[4,5-b]oxirene-4,4-dioxide (19b) ##STR332##

To a solution of 0.4 g of 0.4 g (1.6 mmole) of 18 in 30 mL of methylene chloride was added 2.2 g (3.2 mmole) of 50-60% MCPBA. The reaction mixture was stirred for 2 h and concentrated in vacuo. The residue was dissolved in 30 mL of CHCl₃ and was held at reflux for 18 h under N₂. The reaction mixture was stirred with 100 mL of 10% NaOH and 5 g of sodium sulfite. The methylene chloride layer was washed with brine, dried over MgSO₄ and concentrated in vacuo. The residue was purified by HPLC (20% EtOAc-hexane) to give a third fraction which was further purified by HPLC (10% EtOAc-hexane) to give 0.12 g of syrup in the first fraction. Recrystallization from hexane gave 0.08 g (17%) of 19a, mp 89.5-105.5° C. The mother liquor from the first fraction was combined with the second fraction and was further purified by HPLC to give additional 19a in the first fraction and 60 mg of 19b in the second fraction. Crystallization from hexane gave 56 mg of a white solid.

Example 16 3-Butyl-3-ethyl-4,5-dihydroxy-5-phenyl-2,3,4,5-tetrahydro-benzothiepine-1,1-dioxide (20) ##STR333##

This product was isolated along with 6b from hydrogenation of a mixture of 8a and 8b.

Example 17 3-Butyl-3-ethyl-4-hydroxy-5-phenylthio-2,3,4,5-tetrahydro-benzothiepine-1,1-dioxide (21) ##STR334##

A mixture of 25 mg (0.085 mmole) of 19b, 0.27 g (2.7 mmole) of thiophenol, 0.37 g (2.7 mmole) of potassium carbonate, and 4 mL of DMF was stirred at room temperature under N₂ for 19 h. The reaction mixture was poured into water and extracted with methylene chloride. The methylene chloride layer was washed successively with 10% NaOH and brine, dried over MgSO₄, and concentrated in vacuo to give 0.19 g of semisolid which contain substantial amounts of diphenyl disulfide. This material was purified by HPLC (5% EtOAc-hexane) to remove diphenyl disulfide in the first fraction. The column was then eluted with 20% EtOAc-hexane to give 17 mg of a first fraction, 4 mg of a second fraction and 11 mg of a third fraction which were three different isomers of 21, i.e. 21a, 21b, and 21c, respectively, by ¹ H NMR and mass spectra.

Example 18

Alternative Synthesis of 6c and 6d

A. Preparation from 2-((2-Benzoylphenylthio)methyl)-2-ethylhexanal (2)

Step 1. 2-((2-Benzoylphenylsulfonyl)methyl)-2-ethylhexanal (44) ##STR335##

To a solution of 9.0 g (0.025 mole) of compound 2 in 100 ml of methylene chloride was added 14.6 g (0.025 mol) of 50-60% MCPBA portionwise. The reaction mixture was stirred at room temperature for 64 h then was stirred with 200 ml of 1 M potassium carbonate and filtered through Celite. The methylene chloride layer was washed twice with 300 ml of 1 M potassium carbonate, once with 10% sodium hydroxide and once with brine. The insoluble solid formed during washing was removed by filtration through Celite. The methylene chloride solution was dried and concentrated in vacuo to give 9.2 g (95%) of semisolid. A portion (2.6 g) of this solid was purified by HPLC (10% ethyl acetate-hexane) to give 1.9 g of crystals, mp 135-136° C.

Step 2. 2-((2-Benzylphenylsulfonyl)methyl)-2-ethylhexanal (45) ##STR336##

A solution of 50 g (0.13 mole) of crude 44 in 250 ml of methylene chloride was divided in two portions and charged to two Fisher-Porter bottles. To each bottle was charged 125 ml of methanol and 5 g of 10% Pd/C. The bottles were pressurized with 70 psi of hydrogen and the reaction mixture was stirred at room temperature for 7 h before being charged with an additional 5 g of 10% Pd/C. The reaction mixture was again hydrogenated with 70 psi of hydrogen for 7 h. This procedure was repeated one more time but only 1 g of Pd/C was charged to the reaction mixture. The combined reaction mixture was filtered and concentrated in vacuo to give 46.8 g of 45 as brown oil.

Step 3. (3α,4α,5α) 3-Butyl-3-ethyl-4-hydroxy-5-phenyl-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (6c), and (3α,4β,5β) 3-Butyl-3-ethyl-4-hydroxy-5-phenyl-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (6d)

To a solution of 27.3 g (73.4 mmole) of 45 in 300 ml of anhydrous THF cooled to 2° C. with an ice bath was added 9.7 g (73.4 mmole) of 95% potassium t-butoxide. The reaction mixture was stirred for 20 min, quenched with 300 ml of 10% HCl and extracted with methylene chloride. The methylene chloride layer was dried over magnesium sulfate and concentrated in vacuo to give 24.7 g of yellow oil. Purification by HPLC (ethyl acetate-hexane) yielded 9.4 g of recovered 45 in the first fraction, 5.5 g (20%) of 6c in the second fraction and 6.5 g (24%) of 6d in the third fraction.

B. Preparation from 2-hydroxydiphenylmethane

Step 1. 2-mercaptodiphenylmethane (46) ##STR337##

To a 500 ml flask was charged 16 g (0.33 mol) of 60% sodium hydride oil dispersion. The sodium hydride was washed twice with 50 ml of hexane. To the reaction flask was charged 100 ml of DMF. To this mixture was added a solution of 55.2 g (0.3 mol) of 2-hydroxydiphenylmethane in 200 ml of DMF in 1 h while temperature was maintained below 30° C. by an ice-water bath. After complete addition of the reagent, the mixture was stirred at room temperature for 30 min then cooled with an ice bath. To the reaction mixture was added 49.4 g (0.4 mole) of dimethyl thiocarbamoyl chloride at once. The ice bath was removed and the reaction mixture was stirred at room temperature for 18 h before being poured into 300 ml of water. The organic was extracted into 500 ml of toluene. The toluene layer was washed successively with 10% sodium hydroxide and brine and was concentrated in vacuo to give 78.6 g of a yellow oil which was 95% pure dimethyl O-2-benzylphenyl thiocarbamate. This oil was heated at 280-300° C. in a kugelrohhr pot under house vacuum for 30 min. The residue was kugelrohr distilled at 1 torr (180-280° C.) The distillate (56.3 g) was crystallized from methanol to give 37.3 g (46%) of the rearranged product dimethyl S-2-benzylphenyl thiocarbamate as a yellow solid. A mixture of 57 g (0.21 mole) of this yellow solid, 30 g of potassium hydroxide and 150 ml of methanol was stirred overnight then was concentrated in vacuo. The residue was diluted with 200 ml of water and extracted with ether. The aqueous layer was made acidic with concentrate HCl, The oily suspension was extracted into ether. The ether extract was dried over magnesium sulfate and concentrated in vacuo. The residue was crystallized from hexane to give 37.1 g (88%) of 2-mercaptodiphenylmethane as a yellow solid.

Step 2. 2-((2-Benzylphenylthio)methyl)-2-ethylhexanal (47) ##STR338##

A mixture of 60 g (03 mole) of yellow solid from step 1, 70 g (0.3 mole) of compound 1 from preparation 1, 32.4 g (0.32 mole) of triethylamine, 120 ml of 2-methoxyethyl ether was held at reflux for 6 hr and concentrated in vacuo. The residue was triturated with 500 ml of water and 30 ml of concentrate HCl. The organic was extracted into 400 ml of ether. The ether layer was washed successively with brine, 10% sodium hydroxide and brine and was dried over magnesium sulfate and concentrated in vacuo. The residue (98.3 g) was purified by HPLC with 2-5% ethyl acetate-hexane as eluent to give 2-((2-benzylphenylthio)methyl)-2-ethylhexanal 47 as a yellow syrup.

Step 3. 2-((2-Benzylphenylsulfonyl)methyl)-2-ethylhexanal (45) ##STR339##

To a solution of 72.8 g (0.21 mole) of yellow syrup from step 2 in 1 liter of methylene chloride cooled to 10° C. was added 132 g of 50-60% MCPBA in 40 min. The reaction mixture was stirred for 2 h. An additional 13 g of 50-60% MCPBA was added to the reaction mixture. The reaction mixture was stirred for 2 h and filtered through Celite. The methylene chloride solution was washed twice with 1 liter of 1 M potassium carbonate then with 1 liter of brine. The methylene chloride layer was dried over magnesium sulfate and concentrated to 76 g of 2-((2-benzylphenylsulfonyl)methyl)-2-ethylhexanal 45 as a syrup.

Step 4. (3α,4α,5α) 3-Butyl-3-ethyl-4-hydroxy-5-phenyl-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (6c), and (3α,4β,5β) 3-Butyl-3-ethyl-4-hydroxy-5-phenyl-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (6d)

Reaction of 45 with potassium t-butoxide according to the procedure in step 3 of procedure A gave pure 6c and 6d after HPLC.

Example 19 (3α,4β,5β) 3-Butyl-3-ethyl-4-hydroxy-8-methoxy-5-phenyl-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (25) and (3α,4α,5α) 3-Butyl-3-ethyl-4-hydroxy-8-methoxy-5-phenyl-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (26)

Step 1. Preparation of 2-((2-benzoyl-4-methoxy phenylthio)methyl)-2-ethylhexanal (22) ##STR340##

2-Hydroxy-4-methoxybenzophenone was converted to the dimethyl O-2-benzoyphenyl thiocarbamate by methods previously described in example 18. The product can be isolated by recrystallization from ethanol. Using this improved isolation procedure no chromatography was needed. The thermal rearrangement was performed by reacting the thiocarbamate (5 g) in diphenyl ether at 260° C. as previously described. The improved isolation procedure which avoided a chromatography step was described below.

The crude pyrolysis product was then heated at 65° C. in 100 ml of methanol and 100 ml of THF in the presence of 3.5 g of KOH for 4 h. After removing THF and methanol by rotary evaporation the solution was extracted with 5% NaOH and ether. The base layer was acidified and extracted with ether to obtain a 2.9 g of crude thiophenol product. The product was further purified by titrating the desired mercaptan into base with limited KOH. After acidification and extraction with ether pure 2-mercapto-4-methoxybenzophenone (2.3 g) was isolated.

2-mercapto-4-methoxybenzophenone can readily be converted to the 2-((2-benzoyl-4-methoxyphenylthio)methyl)-2-ethylhexanal (22) by reaction with 2-ethyl-2-(mesyloxymethyl)hexanal (1) as previously described.

Step 2. 2-((2-Benzoyl-5-methoxyphenylsulfonyl)methyl)-2-ethylhexanal (23) ##STR341##

Substrate 22 was readily oxidized to 2-((2-benzoyl-5-methoxyphenyl-sulfonyl)methyl)-2-ethylhexanal (23) as described in example 18.

Step 3. 2-((2-benzyl-5-methoxyphenylsulfonyl)methyl)-2-ethylhexanal (24) ##STR342##

Sulfone 23 was then reduced to 2-((2-benzyl-5-methoxyphenyl-sulfonyl)methyl)-2-ethylhexanal (24) as described in example 18.

Step 4. (3α,4β,5β) 3-Butyl-3-ethyl-4-hydroxy-8-methoxy-5-phenyl-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (25) and (3',4',5α) 3-Butyl-3-ethyl-4-hydroxy-8-methoxy-5-phenyl-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (26) ##STR343##

A 3-neck flask equipped with a powder addition funnel,thermocouple and nitrogen bubbler was charged with 19.8 g (0.05 mole) of sulfone 24 in 100 ml dry THF. The reaction was cooled to -1.6° C. internal temperature by means of ice/salt bath. Slowly add 5.61 g (0.05 mole) of potassium t-butoxide by means of the powder addition funnel. The resulting light yellow solution was maintained at -1.6° C. After 30 min reaction 400 ml of cold ether was added and this solution was extracted with cold 10% HCl. The acid layer was extracted with 300 ml of methylene chloride. The organic layers were combined and dried over magnesium sulfate and after filtration stripped to dryness to obtain 19.9 g of product. ¹ H nmr and glpc indicated a 96% conversion to a 50/50 mixture of 25 and 26. The only other observable compound was 4% starting sulfone 24.

The product was then dissolved in 250 ml of 90/10 hexane/ethyl acetate by warming to 50° C. The solution was allowed to cool to room temperature and in this way pure 26 can be isolated. The crystallization can be enhanced by addition of a seed crystal of 26. After 2 crystallizations the mother liquor which was now 85.4% 25 and has a dry weight of 8.7 g. This material was dissolved in 100 ml of 90/10 hexane/ethyl acetate and 10 ml of pure ethyl acetate at 40 C. Pure 25 can be isolated by seeding this solution with a seed crystal of 25 after storing it overnight at 0 C.

Example 20 (3α,4α,5α) 3-Butyl-3-ethyl-4,8-dihydroxy-5-phenyl-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (27) ##STR344##

In a 25 ml round bottomed flask, 1 g of 26 (2.5 mmoles) and 10 ml methylene chloride were cooled to -78° C. with stirring. Next 0.7 ml of boron tribromide (7.5 mmole) was added via syringe. The reaction was allowed to slowly warm to room temperature and stirred for 6 h. The reaction was then diluted with 50 ml methylene chloride and washed with saturated NaCl and then water. The organic layer was dried over magnesium sulfate. The product (0.88g) 27 was characterized by NMR and mass spectra.

Example 21 General Alkylation of phenol 27

A 25 ml flask was charged with 0.15 g of 27 (0.38 mmole), 5 ml anhydrous DME, 54 mg of potassium carbonate(0.38 mmole) and 140 mg ethyl iodide (0.9 mmole). The reaction was stirred at room temperature overnight. The reaction was diluted with 50 ml ethyl ether and washed with water (25 ml) then 5% NaOH (20 ml) and then sat. NaCl. After stripping off the solvent the ethoxylated product 28 was obtained in high yield. The product was characterized by NMR and mass spectra. This same procedure was used to prepare products listed in table 1 from the corresponding iodides or bromides. For higher boiling alkyl iodides and bromides only one equivalent of the alkyl halide was used. ##STR345##

                  TABLE 1                                                          ______________________________________                                         Compound No.      R                                                            ______________________________________                                         27                H                                                            26                Me                                                           28                Et                                                           29                hexyl                                                        30                Ac                                                           31                (CH2) 6-N-pthalimide                                         ______________________________________                                    

Example 22 (3α,4α,5α) 3-Butyl-3-ethyl-4-hydroxy-7-hydroxyamino-5-phenyl-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (37) and (3α,4β,5β) 3-Butyl-3-ethyl-4-hydroxy-7-hydroxyamino-5-phenyl-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (38)

Step 1. Preparation of 2-chloro-5-nitrodiphenylmethane (32) ##STR346##

Procedure adapted from reference: Synthesis--Stuttgart 9 770-772 (1986) Olah G. Et al

Under nitrogen, a 3 neck flask was charged with 45 g (0.172 mole ) of 2-chloro-5-nitrobenzophenone in 345 ml methylene chloride and the solution was cooled to ice/water temperature. By means of an additional funnel, 150 g (0.172 mole) of trifluoromethane sulfonic acid in 345 ml methylene chloride was added slowly. Next 30 g of triethylsilane (0.172 mole) in 345 ml methylene chloride was added dropwise to the chilled solution. Both addition steps (trifluoromethane sulfonic acid and triethylsilane)were repeated. After the additions were completed the reaction was allowed to slowly warm up to room temperature and stirred for 12 h under nitrogen. The reaction mixture was then poured into a chilled stirred solution of 1600 ml of saturated sodium bicarbonate. Gas evolution occurred. Poured into a 4 liter separatory funnel and separated layers. The methylene chloride layer was isolated and combined with two 500 ml methylene chloride extractions of the aqueous layer. The methylene chloride solution was dried over magnesium sulfate and concentrated in vacuo. The residue was recrystallized from hexane to give 39 g product. Structure 32 was confirmed by mass spectra and proton and carbon NMR.

Step 2. Preparation of 2-((2-benzyl-4-nitrophenylthio)methyl)-2-ethylhexanal (33) ##STR347##

The 2-chloro-5-nitrodiphenylmethane product 32 (40 g, 0.156 mole) from above was placed in a 2 liter 2 neck flask with water condenser. Next 150 ml DMSO and 7.18 g (0.156 mole) of lithium sulfide was added and the solution was stirred at 75° C. for 12 h. The reaction was cooled to room temperature and then 51.7 g of mesylate IV was added in 90 ml DMSO. The reaction mixture was heated to 80° C. under nitrogen. After 12 h monitored by TLC and added more mysylate if necessary.

Continued the reaction until the reaction was completed. Next the reaction mixture was slowly poured into a 1900 ml of 5% acetic aqueous solution with stirring, extracted with 4×700 ml of ether, and dried over MgSO4. After removal of ether, 82.7 g of product was isolated. The material can be further purified by silica gel chromatography using 95% hexane and 5% ethyl acetate. If pure mysylate was used in this step there was no need for further purification. The product 33 was characterized by mass spectra and NMR.

Step 3. Oxidation of the nitro product 33 to the sulfone 2-((2-benzyl-4-nitrophenylsulfonyl)methyl)-2-ethylhexanal (34) ##STR348##

The procedure used to oxidize the sulfide 33 to the sulfone 34 has been previously described.

Step 4. Reduction of 34 to 2-((2-benzyl-4-hydroxyaminophenylsulfonyl)methyl)-2-ethylhexanal (35) ##STR349##

A 15 g sample of 34 was dissolved in 230 ml of ethanol and placed in a 500 ml rb flask under nitrogen. Next 1.5 g of 10 wt. % Pd/C was added and hydrogen gas was bubbled through the solution at room temperature until the nitro substrate 34 was consumed. The reaction could be readily monitored by silica gel TLC using 80/20 hexane/EtOAc. Product 35 was isolated by filtering off the Pd/C and then stripping off the EtOH solvent. The product was characterized by NMR and mass spectra.

Step 5. Preparation of the 2-((2-benzyl-4-N,O-di-(t-butoxy-carbonyl)hydroxyaminophenylsulfonyl)methyl)-2-ethylhexanal (36) ##STR350##

A 13.35 g sample of 35 (0.0344 mole) in 40 ml of dry THF was stirred in a 250 ml round bottomed flask. Next added 7.52 g (0.0344 mole) of di-t-butyl dicarbonate in 7 ml THF. Heated at 60° C. overnight. Striped off THF and redissolved in methylene chloride. Extracted with 1% HCl; and then 5% sodium bicarbonate.

The product was further purified by column chromatography using 90/10 hexane/ethyl acetate and then 70/30 hexane/ethyl acetate. The product 36 was obtained (4.12 g) which appeared to be mainly the di-(t-butoxycarbonyl) derivatives by proton NMR.

Step 6. (3α,4α,5α) 3-Butyl-3-ethyl-4-hydroxy-7-hydroxyamino-5-phenyl-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (37) and (3α,4β,5β) 3-Butyl-3-ethyl-4-hydroxy-7-hydroxyamino-5-phenyl-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (38) ##STR351##

A 250 ml 3-neck round bottomed flask was charged with 4 g of 36 (6.8 mmoles), and 100 ml of anhydrous THF and cooled to -78° C. under a nitrogen atmosphere. Slowly add 2.29 g potassium tert-butoxide(20.4 mmoles) with stirring and maintaining a -78° C. reaction temperature. After 1 h at -78° C. the addition of base was completed and the temperature was brought to -10° C. by means of a ice/salt bath. After 3 h at -10° C., only trace 36 remained by TLC. Next add 35 ml of deionized water to the reaction mixture at -10° C. and stirred for 5 min. Striped off most of the THF and added to separatory funnel and extracted with ether until all of the organic was removed from the water phase. The combined ether phases were washed with saturated NaCl and then dried over sodium sulfate. The only products by TLC and NMR were the two BOC protected isomers of 37 and 38. The isomers were separated by silica gel chromatography using 85% hexane and 15% ethyl acetate; BOC-37 (0.71 g) and BOC-38 (0.78 g).

Next the BOC protecting group was removed by reacting 0.87 g of BOC-38 (1.78 mmoles) with 8.7 ml of 4 M HCl (34.8 mmoles)in dioxane for 30 min. Next added 4.74 g of sodium acetate (34.8 mmoles) to the reaction mixture and 16.5 ml ether and stirred until clear. After transferring to a separatory funnel extracted with ether and water and then dried the ether layer with sodium sulfate. After removing the ether, 0.665 g of 38 was isolated. Isomer 37 could be obtained in a similar procedure.

Example 23 (3α,4α,5α) 3-Butyl-3-ethyl-7-(n-hexylamino)-4-hydroxy-5-phenyl-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (40) and (3α,4β,5β) 3-Butyl-3-ethyl-7-(n-hexylamino)-4-hydroxy-5-phenyl-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (41)

Step 1. 2-((2-Benzyl-4-(n-hexylamino)phenylsulfonyl)methyl)-2-ethylhexanal (39) ##STR352##

In a Fischer porter bottle weighed out 0.5 g of 34 (1.2 mmoles) and dissolved in 3.8 ml of ethanol under nitrogen. Next added 0.1 g of Pd/C and 3.8 ml of hexanal. Seal and pressure to 50 psi of hydrogen gas. Stirred for 48 h. After filtering off the catalyst and removing the solvent by rotary evaporation 39 was isolated by column chromatography (0.16 g) using 90/10 hexane ethyl acetate and gradually increasing the mobile phase to 70/30 hexane/ethyl acetate. The product was characterized by NMR and mass spectra.

Step 2. (3α,4α,5α) 3-Butyl-3-ethyl-7-(n-hexylamino)-4-hydroxy-5-phenyl-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (40) and (3α,4β,5β) 3-Butyl-3-ethyl-7-(n-hexylamino)-4-hydroxy-5-phenyl-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (41) ##STR353##

A 2-neck, 25 ml round bottomed flask with stir bar was charged with 0.158 g 39 (0.335 mmole) and 5 ml anhydrous THF under nitrogen. Cool to -10° C. by means of a salt/water bath. Slowly add 0.113 g of potassium tert butoxide (0.335 mmole). After 15 min at -10° C. all of the starting material was consumed by TLC and only the two isomers 40 and 41 were observed. Next added 5 ml of chilled 10% HCl and stirred at -10° C. for 5 min. Transferred to a separatory funnel and extract with ether. Dried over sodium sulfate. Proton NMR of the dried product (0.143 g) indicated only the presence of the two isomers 40 and 41. The two isomers were separated by silica gel chromatography using 90/10 hexane ethyl acetate and gradually increasing the mobile phase to 70/30 hexane/ethyl acetate. 40 (53.2 mg); 41 (58.9 mg)

Example 24

Quaternization of amine substrates 40 and 41

Amine products such as 40 and 41 can be readily alkylated to quaternary salts by reaction with alkyl halides. For example 40 in DMF with 5 equivalents of methyl iodide in the presence of 2,6 dimethyl lutidine produces the dimethylhexylamino quaternary salt.

Example 25 (3α,4β,5β) 3-Butyl-3-ethyl-4-hydroxy-5-(4-iodophenyl)-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (42) ##STR354##

In a 25 ml round bottomed flask 0.5 g (1.3 mmole) of 6d, 0.67 g of mercuric triflate were dissolved in 20 ml of dry methylene chloride with stirring. Next 0.34 g of Iodine was added and the solution was stirred at room temperature for 30 h. The reaction was then diluted with 50 ml methylene chloride and washed with 10 ml of 1 M sodium thiosulfate; 10 ml of saturated KI; and dried over sodium sulfate. See Tetrahedron, Vol.50, No. 17, pp 5139-5146 (1994) Bachki, F. Et al. Mass spectrum indicated a mixture of 6d , mono iodide 42 and a diiodide adduct. The mixture was separated by column chromatography and 42 was characterized bt NMR and mass spectra.

Example 26 (3α,4β,5β) 3-Butyl-5-(4-carbomethoxyphenyl)-3-ethyl-4-hydroxy-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (43) ##STR355##

A 0.1 g sample of 42 (0.212 mmole), 2.5 ml dry methanol, 38 μl triethylamine (0.275 mmole), 0.3 ml toluene and 37 mg of palladium chloride (0.21 mmole) was charged to a glass lined mini reactor at 300 psi carbon monoxide. The reaction was heated at 100° C. overnight. The catalyst was filtered and a high yield of product was isolated. The product was characterized by NMR and mass spectra.

Note the ester functionalized product 43 can be converted to the free acid by hydrolysis.

Example 27 (3α,4α,5α) 3-Butyl-3-ethyl-4-hydroxy-7-methoxy-5-phenyl-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (48), and (3α,4β,5β) 3-Butyl-3-ethyl-4-hydroxy-7-methoxy-5-phenyl-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (49)

Step 1. 2-Mercapto-5-methoxybenzophenone (50) ##STR356##

Reaction of 66.2 g of 4-methoxythiophenol with 360 ml of 2.5 N n-butyllithium, 105 g of tetramethylethylenediamine and 66.7 g of benzonitrile in 600 ml cyclohexane according to the procedure in WO 93/16055 gave 73.2 g of brown oil which was kugelrohr distilled to remove 4-methoxythiophenol and gave 43.86 g of crude 50 in the pot residue.

Step 2. 2-((2-Benzoyl-4-methoxyphenylthio)methyl)-2-ethylhexanal (51) ##STR357##

Reaction of 10 g (0.04 mole) of crude 50 with 4.8 g (0.02 mole) of mesylate 1 and 3.2 ml (0.23 mole) of triethylamine in 50 ml of diglyme according to the procedure for the preparation of 2 gave 10.5 g of crude product which was purified by HPLC (5% ethyl acetate-hexane) to give 1.7 g (22%) of 51.

Step 3. 2-((2-Benzoyl-4-methoxyphenylsulfonyl)methyl)-2-ethyl-hexanal (52) ##STR358##

A solution of 1.2 g (3.1 mmoles) of 51 in 25 ml of methylene chloride was reacted with 2.0 g (6.2 mmoles) of 50-60% MCPBA according to the procedure of step 2 of procedure A in example 18 gave 1.16 g (90%) of 52 as a yellow oil.

Step 4. 2-((2-Benzyl-4-methoxyphenylsulfonyl)methyl)-2-ethylhexanal (53) ##STR359##

Hydrogenation of 1.1 g of 52 according to the procedure of step 3 of procedure A of example 18 gave 53 as a yellow oil (1.1 g).

Step 5. (3α,4α,5α) 3-Butyl-3-ethyl-4-hydroxy-7-methoxy-5-phenyl-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (48), and (3α,4β,5β) 3-Butyl-3-ethyl-4-hydroxy-7-methoxy-5-phenyl-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (49) ##STR360##

A solution of 1.1 g of 53, 0.36 g of potassium t-butoxide and 25 ml of anhydrous THF was held at reflux for 2 h and worked up as in step 4 of procedure A of example 18 to give 1.07 g of a crude product which was purified by HPLC to give 40 mg (4%) of 48 as crystals, mp 153-154° C. and 90 mg (8%) of 49 as solid, mp 136-140° C.

Example 28 5-Phenyl-2,3-dihydrospirobenzothiepine-3,1'-cyclohexane (57)

Step 1. 1-(Hydroxymethyl)-cyclohexanecarboxaldehyde (54) ##STR361##

To a cold (0° C.) mixture of 100 g (0.891 mole) of cyclohexanecarboxaldehyde, 76.5 g of 37% of formaldehyde in 225 ml of methanol was added dropwise 90 ml of 1 N Sodium hydroxide in 1 h. The reaction mixture was stirred at room temperature over 48 then was evaporated to remove methanol. The reaction mixture was diluted with water and extracted with methylene chloride. The organic layer was washed with water, brine, and dried over sodium sulfate and concentrated under vacuum to give 75 g (59.7%) of thick oil. Proton NMR and mass spectra were consistent with the product.

Step 2. 1-(mesyloxymethyl)cyclohexanecarboxaldehyde (55) ##STR362##

To a cold (0° C.) mixture of alcohol 54 (75 g, 0.54 mole) and 65.29 g (0.37 mole) of methanesulfonyl chloride in 80 ml of methylene chloride was added a solution of pyridine (47.96 g, 0.57 mole) in 40 ml of methylene chloride. The reaction mixture was stirred at room temperature for 18 h then quenched with water, acidified with conc. HCl and extracted with methylene chloride. The organic layer was washed with water, brine, and dried over sodium sulfate and concentrated under vacuum to give 91.63 g (77.8%) of thick oil. Proton NMR and mass spectra were consistent with the product.

Step 3. 1-((2-Benzoylphenylthio)methyl)cyclohexanecarboxaldehyde (56) ##STR363##

A mixture of 69 g (0.303 mole) of 2-mercaptobenzophenone, 82 g (0.303 mole) of mesylate 55, 32 g of triethylamine, and 150 ml of diglyme was stirred and held at reflux for 24 h. The mixture was cooled, poured into dil. HCl and extracted with methylene chloride. The organic layer was washed with 10% NaOH, water, brine, and dried over sodium sulfate and concentrated under vacuum to remove excess diglyme. This was purified by silica gel flush column (5% EtOAc:Hexane) and gave 18.6 g (75.9%) of yellow oil. Proton NMR and mass spectra were consistent with the product.

Step 4. 5-Phenyl-2,3-dihydrospirobenzothiepine-3,1'-cyclohexane (57) ##STR364##

To a mixture of 6.19 g of zinc dust and 100 ml of dry DME was added TiCl₃ (16.8 g, 0.108 mole). The reaction mixture was heated to reflux for 2 h. A solution of compound 56 (8.3 g, 0.023 mole) in 50 ml of DME was added dropwise to the reaction mixture in 1 h and the mixture was held at reflux for 18 h. The mixture was cooled, poured into water and extracted with ether. The organic layer was washed with water, brine, and dried over sodium sulfate, filtered through celite and concentrated under vacuum. The residue was purified by HPLC (10% EtOAc:Hexane) to give 4.6 g (64%) of white solid, mp 90-91° C. Proton and carbon NMR and mass spectra were consistent with the product.

Example 29 8b-Phenyl-1a,2,3,8b-tetrahydrospiro(benzothiepino[4,5-b]oxirene-2,1'-cyclohexane)-4,4-dioxide (58) ##STR365##

To a solution of 57 (4.6 g, 15 mmole) in 50 ml chloroform under nitrogen was added 55% MCPBA (16.5 g, 52.6 mmole) portionwise with spatula. The reaction was held at reflux for 18 h and washed with 10% NaOH (3×), water, brine, and dried over sodium sulfate and concentrated under vacuum to give 5 g of crude product. This was recrystallized from Hexane/EtOAc to give 4.31 g (81%) of yellow solid, mp 154-155° C. Proton and carbon NMR and mass spectra were consistent with the product.

Example 30 trans-4-Hydroxy-5-phenyl-2,3,4,5-tetrahydro spiro(benzothiepine-3,1'-cyclohexane)-1,1-dioxide (59) ##STR366##

A mixture of 0.5 g (1.4 mmoles) of 58, 20 ml of ethanol, 10 ml of methylene chloride and 0.4 g of 10% Pd/C catalyst was hydrogenated with 70 psi hydrogen for 3 h at room temperature. The crude reaction slurry was filtered through Celite and evaporated to dryness. The residue was purified by HPLC (10% EtOAc-Hexane, 25% EtOAc-Hexane). The first fraction was 300 mg (60%) as a white solid, mp 99-100° C. Proton NMR showed this was a trans isomer. The second fraction gave 200 mg of solid which was impure cis isomer.

Example 31 cis-4-Hydroxy-5-phenyl-2,3,4, 5-tetrahydro spiro(benzothiepine-3,1'-cyclohexane)-1,1-dioxide (60) ##STR367##

To a solution of 0.2 g (0.56 mmole) of 59 in 20 ml of CH₂ Cl₂, was added 8 g of 50% NaOH and one drop of Aliquat-336 (methyltricaprylylammonium chloride) phase transfer catalyst. The reaction mixture was stirred for 10 h at room temperature. Twenty g of ice was added to the mixture and the mixture was extracted with CH₂ Cl₂ (3×10 ml) washed with water, brine and dried over MgSO₄ and concentrated in vacuo to recover 0.15 g of crude product. This was recrystallized from Hexane/EtOAc to give 125 mg of white crystal, mp 209-210° C. Proton and carbon NMR and mass spectra were consistent with the product.

Example 32 (3α,4α,5α) 3-Butyl-3-ethyl-4-hydroxy-5-phenyl-2,3,4,5-tetrahydrobenzothiepine (61), and (3α,4β,5β) 3-Butyl-3-ethyl-4-hydroxy-5-phenyl-2,3,4,5-tetrahydrobenzothiepine (62) ##STR368##

To a solution of 0.5 g (1.47 mmole) of compound 47 in 5 ml of anhydrous THF was added 0.17 g (1.47 mmole) of 95% potassium t-butoxide. The reaction mixture was stirred at room temperature for 18 h and quenched with 10 ml of 10% HCl. The organic was extracted into methylene chloride. The methylene chloride extract was dried over magnesium sulfate and concentrated in vacuo. The residue was purified by HPLC (2% EtOAc-hexane) to give 47 mg of 61 in the second fraction and 38 mg of 62 in the third fraction. Proton NMR and mass spectra were consistent with the assigned structures.

Example 33 (3α,4α,5α) 3-Butyl-3ethyl-4-hydroxy-7-amino-5-phenyl-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (63) and (3α,4β,5β) 3-Butyl-3-ethyl-4-hydroxy-7-amino-5-phenyl-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide(64) ##STR369##

An autoclave was charged with 200 mg of 37 in 40 cc ethanol and 0.02 g 10% Pd/C. After purging with nitrogen the clave was charged with 100 psi hydrogen and heated to 55° C. The reaction was monitored by TLC and mass spec and allowed to proceed until all of 37 was consumed. After the reaction was complete the catalyst was filtered and the solvent was removed in vacuo and the only observable product was amine 63. This same procedure was used to produce 64 from 38.

Example 34 (3α,4α,5α) 3-Butyl-3-ethyl-4-hydroxy-7-methoxy-5-(3'-methoxyphenyl)-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (65), and (3α,4β,5β) 3-Butyl-3-ethyl-4-hydroxy-7-methoxy-5-(3'-methoxyphenyl)-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (66) ##STR370##

Alkylation of e-methoxyphenol with 3-methoxybenzyl chloride according to the procedure described in J. Chem. Soc, 2431 (1958) gave 4-methoxy-2-(3'-methoxybenzyl)phenol in 35% yield. This material was converted to compound 65, mp 138.5-141.5° C., and compound 66, mp 115.5-117.5° C., by the procedure similar to that in Example 18 method B.

Example 35 (3α,4α,5α) 3-Butyl-3-ethyl-4-hydroxy-7-methoxy-5-(3'-(trifluoromethyl)phenyl)-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (67), and (3α,4β,5β) 3-Butyl-3-ethyl-4-hydroxy-7-methoxy-5-(3'-(trifluoromethyl)phenyl)-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (68) ##STR371##

Alkylation of 4-methoxyphenol with 3-(trifluoromethyl)benzyl chloride according to the procedure described in J. Chem. Soc. 2431 (1958) gave 4-methoxy-2-(3'-(trifluoromethyl)benzyl)phenol. This material was converted to compound 67, mp 226.5-228° C., and compound 68, mp 188-190° C., byu the procedure similar to that in Example 18 method B.

Example 36 (3α,4α,5α) 3-Butyl-3-ethyl-5-(4'-fluorophenyl)-4-hydroxy-7-methoxy-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (69), and (3α,4β,5β) 3-Butyl-3-ethyl-5-(4'-fluorophenyl)-4-hydroxy-7-methoxy-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (70) ##STR372##

Alkylation of 4-methoxyphenol with 4-fluorobenzyl chloride according to the procedure described in J. Chem. Soc, 2431 (1958) gave 4-methoxy-2-(4'-fluorobenzyl)phenol. This material was converted to compound 69 and compound 70 by the procedure similar to that in Example 18 method B.

Example 37 (3α,4α,5α) 3-Butyl-3-ethyl-5-(3'-fluorophenyl)-4-hydroxy-7-methoxy-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (71), and (3α,4β,5β) 3-Butyl-3-ethyl-5-(3'-fluorophenyl)-4-hydroxy-7-methoxy-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (72) ##STR373##

Alkylation of 4-methoxyphenol with 3-fluorobenzyl chloride according to the procedure described in J. Chem. Soc, 2431 (1958) gave 4-methoxy-2-(3'-fluorobenzyl)phenol. This material was converted to compound 71 and compound 72 by the procedure similar to that in Example 18 method B.

Example 38 (3α,4α,5α) 3-Butyl-3-ethyl-5-(2'-fluorophenyl)-4-hydroxy-7-methoxy-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (73), and (3α,4β,5β) 3-Butyl-3-ethyl-5-(2'-fluorophenyl)-4-hydroxy-7-methoxy-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (74) ##STR374##

Alkylation of 4-methoxyphenol with 2-fluorobenzyl chloride according to the procedure described in J. Chem. Soc, 2431 (1958) gave 4-methoxy-2-(2'-fluorobenzyl)phenol. This material was converted to compound 73 and compound 74 by the procedure similar to that in Example 18 method B.

Example 39 (3α,4α,5α) 3-Butyl-7-bromo-3-ethyl-4-hydroxy-5-(3'-methoxyphenyl)-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (75), and (3α,4β,5β) 3-Butyl-7-bromo-3-ethyl-4-hydroxy-5-(3'-methoxyphenyl)-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (76) ##STR375##

Alkylation of 4-bromophenol with 3-methoxybenzyl chloride according to the procedure described in J. Chem. Soc, 2431 (1958) gave 4-bromo-2-(3'-methoxybenzyl)phenol. This material was converted to compound 75, mp 97-101.5° C., and compound 76, mp 102-106° C., by the procedure similar to that in Example 18 method B.

Example 40 (3α,4α,5α) 3-Butyl-3-ethyl-7-fluoro-5-(4'-fluorophenyl)-4-hydroxy-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (77), and (3α,4β,5β) 3-Butyl-3-ethyl-7-fluoro-5-(4'-fluorophenyl)-4-hydroxy-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (78) ##STR376##

Alkylation of 4-fluorophenol with 4-fluorobenzyl chloride according to the procedure described in J. Chem. Soc, 2431 (1958) gave 4-fluoro-2-(4'-fluorobenzyl)phenol. This material was converted to compound 77, mp 228-230° C., and compound 78, mp 134.5-139° C., by the procedure similar to that in Example 18 method B.

Example 41 (3α,4α,5α) 3-Butyl-3-ethyl-7-fluoro-4-hydroxy-5-(3'-methoxyphenyl)-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (79), and (3α,4β,5β) 3-Butyl-3-ethyl-7-fluoro-40hydroxy-5-(3'-methoxyphenyl)-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (80) ##STR377##

Alkylation of 4-fluorophenol with 3-methoxybenzyl chloride according to the procedure described in J. Chem. Soc, 2431 (1958) gave 4-fluoro-2-(3'-methoxybenzyl)phenol. This material was converted to compound 79, as a solid and compound 80, mp 153-155° C., by the procedure similar to that in Example 18 method B.

Example 42 (3α,4β,5β) 3-Butyl-3-ethyl-5-(4'-fluorophenyl)-4-hydroxy-7-methylthio-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (81). ##STR378##

A mixture of 0.68 (1.66 mmol) of compound 77, 0.2 g (5 mmol) of sodium methanethiolate and 15 ml of anhydrous DMF was stirred at room temperature for 16 days. The reaction mixture was dilute with ether and washed with water and brine and dried over M_(g) SO₄. The ether solution was concentrated in vacuo. The residue was purified by HPLC (20% ethyl acetate in hexanes). The first fraction was impure (3α,4α,5α) 3-butyl-3-ethyl-4-hydroxy-7-methylthio-5-(4'-fluorophenyl)-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide. The second fraction was compound 81, mp 185-186.5° C.

Example 43 (3α,4β,5β) 3-Butyl-3-ethyl-5-(4'-fluorophenyl)-4-hydroxy-7-(1-pyrrolidinyl)-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (82). ##STR379##

A mixture of 0.53 g (1.30 mmol) of compound 78 and 5 ml of pyrrolidine was held at reflux for 1 h. The reaction mixture was diluted with ether and washed with water and brine and dried over M_(g) SO₄. The ether solution was concentrated in vacuo. The residue was crystallized from ether-hexanes to give compound 82, mp 174.5-177° C.

Example 44 (3α,4β,5β) 3-Butyl-3-ethyl-5-(4'-fluorophenyl)-4-hydroxy-7-(1-morpholinyl)-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (83) ##STR380##

A mixture of 0.4 g (0.98 mmol) of compound 78 and 5.0 g (56 mmol) of morpholine was held at reflux for 2 h and concentrated in vacuo. The residue was diluted with ether (30 ml) and washed with water and brine and dried over M_(g) SO₄. The ether solution was concentrated in vacuo. The residue was recrystallized from ether-hexanes to give compound 83, mp 176.5-187.5° C.

Example 45 (3α,4α,5α) 3-Butyl-3-ethyl-5-(4'-fluorophenyl)-4-hydroxy-7-methyl-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (84), and (3α,4β,5β) 3-Butyl-3-ethyl-5-(4'-fluorophenyl)-4-hydroxy-7-methyl-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (85) ##STR381##

Alkylation of 4-methylphenol with 4-fluorobenzyl chloride according to the procedure described in J. Chem. Soc, 2431 (1958) gave 4-methyl-2-(4'-fluorobenzyl)phenol). This material was converted to compound 84 and compound 85 by the procedure similar to that in Example 18 method B.

Example 46 (3α,4β,5β) 3-Butyl-3-ethyl-4-hydroxy-5-(4'-hydroxyphenyl)-7-methoxy-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (86), and (3α,4β,5β) 3-Butyl-3-ethyl-4,7-dihydroxy-5-(4'-hydroxyphenyl)-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (87) ##STR382##

To a solution of 0.52 (1.2 mmol) of compound 66 in 20 ml of methylene chloride was added 1.7 g (6.78 mmol) of born tribromide. The reaction mixture was cooled to -78° C. and was stirred for 4 min. An additional 0.3 ml of boron tribromide was added to the reaction mixture and the reaction mixture was stirred at -78° C. for 1 h and quenced with 2 N HCl. The organic was extracted into ether. The ether layer was washed with brine, dried over M_(g) SO₄, and concentrated in vacuo. The residue (0.48 g) was purified by HPLC (30% ethyl acetate in hexanes). The first fraction was 0.11 g of compound 86 as a white solid, mp 171.5-173° C. The second fraction was crystallized from chloroform to give 0.04 g of compound 87 as a white solid, mp 264° C. (dec).

Example 47 (3α,4β,5β) 3-Butyl-3-ethyl-4,7-dihydroxy-5-(4'-fluorophenyl)-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (88) ##STR383##

Reaction of compound 70 with excess boron tribromide at room temperature and worked up as in Example 46 gave compound 88 after an HPLC purification.

Example 48 (3α,4β,5β) 3-Butyl-3-ethyl-5-(4'-fluorophenyl)-4-hydroxy-7-(1-azetidinyl)-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (89) ##STR384##

A mixture of 0.20 g (0.49 mmol) of compound 78, and 2.0 g (35 mmol) of aztidine was held at reflux for 3 h and concentrated in vacuo. The residue was diluted with ether (30 ml) and washed with water and brine and dried over MgSO₄. The ether solution was concentrated on a steam bath. The separated crystals were filtered to give 0.136 g of 89 as prisms, mp 196.5-199.5° C.

Example 49 (3α,4α,5α) 3-Butyl-3-ethyl-5-(3'-methoxyphenyl)-4-hydroxy-7-methylthio-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (90). (3α,4β,5β) 3-Butyl-3-ethyl-5-(3'-methoxyphenyl)-4-hydroxy-7-methylthio-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (91) ##STR385##

A mixture of 0.4 g (0.95 mmol) of compound 79, 0.08 g (1.14 mmol) of sodium methanethiolate and 15 ml of anhydrous DMF was stirred at 60° C. for 2 h. An additional 1.4 mmol of sodium methanethiolate was added to the reaction mixture and the mixture was stirred at 60° C. for an additional 2 h. The reaction mixture was triturated with 100 ml of water and extracted methylene chloride. The methylene chloride water mixture was filtered through Celite and the methylene chloride layer was dried over M_(g) SO₄ and concentrated in vacuo. The first fraction (0.1 g) was compound 90, mp 117-121° C. The second fraction (0.16 g) was compound 91, mp 68-76° C.

Example 50

Preparation of polyethyleneglycol functionalized benzothiepine A ##STR386##

A 50 ml rb flash under a nitrogen atmosphere was charged with 0.54 g of M-Tres-5000 (Polyethyleneglycol Tresylate [methoxy-PEG-Tres,MW 5000] purchased from Shearwater Polymers Inc., 2130 Memorial Parkway, SW, Huntsville, Ala. 35801), 0.055 g Compound No. 136, 0.326 C_(s) CO₃ and 2 cc anhydrous acetonitrile. The reaction was stirred at 30 C. for 5 days and then the solution was filtered to remove salts. Next, the acetonitrile was removed under vacuum and the product was dissolved in THF and then precipitated by addition of hexane. The polymer precipitate was isolate by filtration from the solvent mixture (THF/hexane). This precipitation procedure was continued until no Compound No. 136 was detected in the precipitated product (by TLC SiO2). Next, the polymer precipitate was dissolved in water and filtered and the water soluble polymer was dialyzed for 48 hours through a cellulose dialysis tube (Spectrum® 7 ,45 mm×0.5 ft, cutoff 1,000 MW). The polymer solution was then removed from the dialysis tube and lyophilized until dried. The NMR was consistent with the desired product A and gel permeation chromatography indicated the presence of a 4500 MW polymer and also verified that no free Compound No. 136 was present. This material was active in the IBAT in vitro cell assay.

Example 51

Preparation of Compound 140 ##STR387##

A 2-necked 50 ml round bottom Flask was charged with 0.42 g of Tres-3400 (Polyethyleneglycol Tresylate [Tres-PEG-Tres,MW 3400] purchased from Shearwater Polymers Inc., 2130 Memorial Parkway, SW, Huntsville, Ala. 35801), 0.1 potassium carbonate, 0.100 g of Compound No. 111 and 5 ml anhydrous DMF. Stir for 6 days at 27° C. TLC indicated the disappearance of the starting Compound No. 111. The solution was transferred to a separatory funnel and diluted with 50 cc methylene chloride and then extracted with water. The organic layer was evaporated to dryness by means of a rotary evaporator. Dry wgt. 0.4875 g. Next, the polymer was dissolved in water and then dialyzed for 48 hours at 40° C. through a cellulose dialysis tube (spectrum® 7, 45 mm×0.5 ft, cutoff 1,000 MW). The polymer solution was then removed from the dialysis tube and lyophilized until dried 0.341 g). NMR was consistent with the desired product B.

Example 52 ##STR388##

A 10 cc vial was charged with 0.21 g of Compound No. 136 (0.5 mmoles), 0.17 g (1.3 mmoles)potassium carbonate, 0.6 g (1.5 mmoles) of 1,2-bis-(2-iodoethoxy)-ethane and 10 cc DMF. The reaction was stirred for 4 days at room temperature and then worked up by washing with ether/water. The ether layer was stripped to dryness and the desired product Compound No. 134 was isolated on a silica gel column using 80/20 hexane ethyl acetate.

Example 53 ##STR389## Example 54 ##STR390##

A two necked 25 ml round bottom Flask was charged with 0.5 g (1.24 mmoles) of 69462, 13 mls of anhydrous DMF, 0.055 g of 60% NaH dispersion and 0.230 g (0.62 mmoles) of 1,2-Bis[2-iodoethoxylethane] at 10° C. under nitrogen. Next, the reaction was slowly heated to 40° C. After 14 hours all of the Compound No. 113 was consumed and the reaction was cooled to room temperature and extracted with ether/water. The ether layer was evaporated to dryness and then chromatographed on Silicage (80/20 ethyl acetate/hexane). Isolated Compound No. 112 (0.28 g) was characterized by NMR and mass spec.

Example 55 ##STR391##

In a 50 ml round bottom Flask, add 0.7 g (1.8 mmoles) of Compound No. 136, 0.621 g of potassium carbonate, 6 ml DMF, and 0.33 g of 1,2-Bis[2-iodoethoxylethane]. Stir at 40° C. under nitrogen for 12 hours. The workup and isolation was the same procedure for Compound No. 112.

Examples 56 and 57 (Compound Nos. 131 and 137)

The compositions of these compounds are shown in Table 3.

The same procedure as for Example 55 except appropriate benzothiepine was used.

Example 58 (Compound No. 139)

The composition of this compound is shown in Table 3. Same procedure as for Example 55 with appropriate benzothiepine 1,6 diiodohexane was used instead of 1,2-Bis[2-iodoethoxylethane].

Example 59 (Compound No. 101) ##STR392##

This compound is prepared by condensing the 7-NH₂ benzothiepine with the 1,12-dodecane dicarboxylic acid or acid halide.

Example 60 (Compound No. 104) ##STR393##

2-Chloro-4-nitrobenzophenone is reduced with triethylsilane and trifluoromethane sulfonic acid to 2-chloro-4-nitrodiphenylmethane 32. Reaction of 32 with lithium sulfide followed by reacting the resulting sulfide with mesylate IV gives sulfide-aldehyde XXIII. Oxidation of XXIII with 2 equivalents of MCPBA yields sulfone-aldehyde XXIV (see Scheme 5). Reduction of the sulfone-aldehyde XXV formaldehyde and 100 psi hydrogen and 55 C. for 12 hours catalyzed by palladium on carbon in the same reaction vessel yields the substituted dimethylamine derivative XXVIII. Cyclization of XXVII with potassium t-butoxide yields a mixture of substituted amino derivatives of this invention Compound No. 104. ##STR394##

Example 61 ##STR395##

A 1 oz. Fisher-porter bottle was charged with 0.14 g (0.34 mmoles) of 70112, 0.97 gms (6.8 mmoles) of methyl iodide, and 7 ml of anhydrous acetonitrile. Heat to 50° C. for 4 days. The quat. Salt Compound No. 192 was isolated by concentrating to 1 cc acetonitrile and then precipitating with diethyl ether.

Example 62 ##STR396##

A 0.1 g (0.159 mmoles) sample of Compound No. 134 was dissolved in 15 ml of anhydrous acetonitrile in a Fischer-porter bottle and then trimethylamine was bubbled through the solution for 5 minutes at 0° C. and then capped and warmed to room temperature. The reaction was stirred overnight and the desired product was isolated by removing solvent by rotary evaporation.

Example 63 (Compound No. 295) ##STR397##

Sodium Hydride 60% (11 mg, 0.27 mmoles) in 1 cc of acetonitrile at 0° C. was reacted with 0.248 mmoles (.10 g) of Compound No. 54 in 2.5 cc of acetonitrile at 0° C. Next, 0.(980 g 2.48 mmoles) of 1,2-Bis[2-iodoethoxylethane]. After warming to room temperature, stir for 14 hours. The product was isolated by column chromatography.

Example 64 (Compound No. 286) ##STR398##

Following a procedure similar to the one described in Example 86, infra (see Compound No. 118), the title compound was prepared and purified as a colorless solid; mp 180-181° C; ¹ H NMR (CHCl₃) δ 0.85 (t, J=6 Hz, 3H₋₋, 0.92 (t, J=6 Hz, 3H), 1.24-1.42 (m, 2H), 1.46-1.56 (m, 1H), 1.64-1.80 (m, 1H), 2.24-2.38 (m, 1H), 3.15 (AB, J_(AB) =15 Hz, Δv=42 Hz, 2H), 4.20 (d, J=8 Hz, 1H), 5.13 (s, 2H), 5.53 (s, 1H), 6.46 (s, 1H), 6.68 (s, 1H), 7.29-7.51 (m, 10H), 7.74 (d, J=8 Hz, 1H), 8.06 (d, J=8 Hz, 1H). FABMS m/z 494 (M+H), HRMS calcd for (M+H) 494.2001, found 494.1993. Anal. Calcd. for C₂₈ H₃₁ NO₅ S: C, 68.13; H, 6.33; N, 2.84. Found: C, 68.19; H, 6.56; N, 2.74.

Example 65 (Compound No. 287) ##STR399##

Following a procedure similar to the one described in Example 89, infra (see Compound No. 121), the title compound was prepared and purified as a colorless solid: mp 245-246° C., ¹ H NMR (CDCl₃) δ 0.84 (t, J=6 Hz, 3H), 0.92 (t, J=6 Hz, 3H), 1.28, (d, J=8 Hz, 1H), 1.32-1.42 (m, 1H), 1.48-1.60 (m, 1H), 1.64-1.80 (m, 1H), 2.20-2.36 (m, 1H), 3.09 (AB, J_(AB) =15 Hz, Δv=42 Hz, 2H), 3.97 (bs, 2H), 4.15 (d, J=8 Hz, 1H), 5.49 (s, 1H), 5.95 (s, 1H), 6.54 (d, J=7 Hz, 1H), 7.29-7.53 (m, 5H), 7.88 (d, J=8 Hz, 1H); ESMS 366 (M+Li). Anal. Calcd. for C₂₀ H₂₅ NO₃ S: C, 66.82; H, 7.01; N, 3.90. Found: C, 66.54; H, 7.20; N, 3.69.

Example 66 (Compound No. 288) ##STR400##

Following a procedure similar to the one described in Example 89, infra (see Compound No. 121), the title compound was prepared and purified by silica gel chromatography to give the desired product as a colorless solid: mp 185-186° C.; ¹ H NMR (CDCl₃) δ 1.12 (s, 3H), 1.49 (s, 3H), 3.00 (d, J=15 Hz, 1H), 3.28 (d, J=15 Hz, 1H), 4.00 (s, 1H), 5.30 (s, 1H), 5.51 (s, 1H), 5.97 (s, 1H), 6.56 (dd, J=2.1, 8.4 Hz, 1H), 7.31-7.52 (m, 5H), 7.89 (d, J=8.4 Hz, 1H). MS (FAB+) (M+H) m/z 332.

Example 67 (Compound No. 289) ##STR401##

Following a procedure similar to the one described in Example 89 (see Compound No. 121), the title compound was prepared and purified by silica gel chromatography to give the desired product as a white solid: mp 205-206° C.; ¹ H NMR (CDCl₃) δ 0.80-0.95 (m, 6H), 1.10-1.70 (m, 7H), 2.15 (m, 1H), 3.02 (d, J=15.3 Hz, 2H), 3.15 (d, J=15.1 Hz, 2H), 3.96 (s, br, 2H), 4.14 (d, J=7.8 Hz, 1H), 5.51 (s, 1H), 5.94 (d, J=2.2, 1H), 6.54 (dd, J=8.5, 2.2 Hz, 1H), 7.28-7.50 (m, 6H), 7.87 (d, J=8.5 Hz, 1H). MS (FAB): m/z 388 (M+H).

Example 68 (Compound No. 290) ##STR402##

Following a procedure similar to the one described in Example 89, infra (see Compound No. 121), the title compound was prepared and purified as a colorless solid: mp=96-98° C., ¹ H NMR (CDCl₃) δ 0.92 (t, J=7 Hz, 6H), 1.03-1.70 (m, 11H), 2.21 (t, J=8 Hz, 1H), 3.09 (AB, J_(AB) =-18 Hz, Δv=38 Hz, 2H), 3.96 (bs, 2H), 4.14 (d, J=7 Hz, 1H), 5.51 (s, 1H), 5.94 (s, 1H), 6.56 (d, J=9 Hz, 1H), 7.41-7.53 (m, 6H), 7.87 (d, J=8 Hz, 1H); FABMS m/z 416 (M+H).

Example 69 ##STR403##

Following a procedure similar to the one described in Example 86, infra (see Compound No. 118), the title compound was prepared and purified as a colorless solid: ¹ H NMR (CDCl₃) δ 0.91 (t, J=7 Hz, 6H), 1.02-1.52 (m, 11H), 1.60-1.70 (m, 1H), 2.23 (t, J=8 Hz, 1H), 3.12 (AB, J_(AB) =18 Hz, Δv=36 Hz, 2H), 4.18 (d, J=7 Hz, 1H), 5.13 (s, 2H), 5.53 (s, 1H), 6.43 (s, 1H), 6.65 (s, 1H), 7.29-7.52 (m, 10H), 7.74 (d, J=9 Hz, 1H), 8.03 (d, J=8 Hz, 1H); ESMS m/z 556 (M+Li).

Example 70 (Compound No. 292) ##STR404##

Following a procedure similar to the one described in Example 89, infra (see Compound No. 121), the title compound was prepared and purified as a colorless solid: mp=111-112.5° C., ¹ H NMR (CDCl₃) δ 0.90 (t, J=8 Hz, 6H), 1.03-1.50 (m, 10H), 1.55-1.70 (m, 2H), 2.18 (t, J=12 Hz, 2H), 3.07 (AB, J_(AB) =15 Hz, Δv=45 Hz, 2H), 4.09 (bs, 2H), 5.49 (s, 1H), 5.91 (s, 1H), 6.55 (d, J=9 Hz, 1H), 7.10 (t, J=7 Hz, 2H), 7.46 (t, J=6 Hz, 2H), 7.87 (d, J=9 Hz, 1H).

Example 71 (Compound No. 293) ##STR405##

During the preparation of Compound No. 290 from Compound No. 291 using BBr₃, the title compound was isolated: ¹ H NMR (CDCl₃) δ 0.85 (t, J=6 Hz, 6H), 0.98-1.60 (m, 10H), 1.50-1.66 (m, 2H), 2.16 (t, J=8 Hz, 1H), 3.04 (AB, J_(AB) =15 Hz, Δv=41 Hz, 2H), 4.08 (s, 1H), 4.12 (s, 1H), 5.44 (s, 1H), 5.84 (s, 1H), 6.42 (d, J=9 Hz, 1H), 7.12 (d, J=8 Hz, 2H), 7.16-7.26 (m, 10H), 7.83 (d, J=8 Hz, 1H); ESMS m/z 512 (M+Li)

Example 72 (Compound No. 294)

Following a procedure similar to the one described in Example 60 (Compound No. 104), the title compound was prepared and purified as a colorless solid: ¹ H NMR (CDCl₃) δ 0.90 (t, J=6 Hz, 6H), 1.05-1.54 (m, 9H), 1.60-1.70 (m, 1H), 2.24 (t, J=8 Hz, 1H), 2.80 (s, 6H), 3.05 (AB, J_(AB) =15 Hz, Δv=42 Hz, 2H), 4.05-4.18 (m, 2H), 5.53 (s, 1H), 5.93 (s, 1H), 6.94 (d, J=9 Hz, 1H), 7.27-7.42 (m, 4H), 7.45 (d, J=8 Hz, 2H), 7.87 (d, J=9 Hz, 1H); ESMS m/z 444 (M+H).

Structures of the compounds of Examples 33 to 72 are shown in Tables 3 and 3A.

Examples 73-79, 87, 88 and 91-102

Using in each instance a method generally described in those of Examples 1 to 72 appropriate to the substituents to be introduced, compounds were prepared having the structures set forth in Table 3. The starting materials illustrated in the reaction schemes shown above were varied in accordance with principles of organic synthesis well known to the art to introduce the indicated substituents in the 4- and 5-positions (R³, R⁴, R⁵, R⁶) and in the indicated position on the benzo ring (R^(x)).

Structures of the the compounds produced in Examples 73-102 are set forth in Tables 3 and 3A.

Examples 80-84

Preparation of 115, 116, 111, 113

Preparation of 4-chloro-3-[4-methoxy-phenylmethyl]-nitrobenzene

In a 500 ml 2-necked rb flask weigh out 68.3 gms phosphorus pentachloride (0.328 mole 1.1 eq). Add 50 mls chlorobenzene. Slowly add 60 gms 2-chloro-5-nitrobenzoic acid (0.298 mole). Stir at room temp overnight under N2 then heat 1 hr at 50° C.

Remove chlorobenzene by high vacuum. Wash residue with hexane. Dry wt=55.5 gms.

In the same rb flask, dissolve acid chloride (55.5 g 0.25 mole) from above with 100 mls anisole (about 3.4 eq). Chill solution with ice bath while purging with N2. Slowly add 40.3 g aluminum chloride (1.2 eq 0.3 mole). Stir under N₂ for 24 hrs.

After 24 hrs, the solution was poured into 300 mls 1N HCl soln. (cold). Stir this for 15 min. Extract several times with diethyl ether. Extract organic layer once with 2% aqueous NaOH then twice with water. Dry organic layer with MgSO₄, dry on vac line. Solid is washed well with ether and then ethanol before drying. Wt=34.57 g (mixture of mete, ortho and para).

    ______________________________________                                         Elemental       theory  found                                                  ______________________________________                                         C               57.65   57.45                                                  H               3.46    5.51                                                   N               4.8     4.8                                                    Cl              12.15   12.16                                                  ______________________________________                                    

With the next step of the reduction of the ketone with trifluoromethane sulfonic aid and triethyl silane, crystallization with ethyl acetate/hexane affords pure 4-chloro-3-[4-methoxy-phenylmethyl]-nitrobenzene.

4-Chloro-3-[4-methoxy-phenylmethyl]-nitrobenzene was then reacted as specified in the synthesis of 117 and 118 from 2-chloro-4-nitrophenylmethane. From these procedures 115 and 116 can be synthesized. Compounds 111 and 113 can be synthesized from the procedure used to prepare compound 121.

Compound 114 can be prepared by reaction of 116 with ethyl mercaptan and aluminum trichloride.

Examples 85 and 86

Preparation of 117 and 118

2-Chloro-4-nitrobenzophenone is reduced with triethylsilane and trifluoromethane sulfonic acid to 2-chloro-4-nitrodiphenylmethane 32. Reaction of 32 with lithium sulfide followed by reacting the resulting sulfide with mesylate IV gives sulfide-aldehyde XXIII. Oxidation of XXIII with 2 equivalents of MCPBA yields sulfone-aldehyde XXIII. Oxidation of XXIII with 2 equivalents of MCPBA yields sulfone-aldehyde XXIV (see Scheme 5).

The sulfone-aldehyde (31.8 g) was dissolved in ethanol/toluene and placed in a parr reactor with 100 ml toluene and 100 ml of ethanol and 3.2 g of 10% Pd/C and heated to 55 C. and 100 psi of hydrogen gas for 14 hours. The reaction was then filtered to remove the catalyst. The amine product (.076 moles, 29.5 g) from this reaction was then reacted with benzyl chloroformate (27.4 g) in toluene in the presence of 35 g of potassium carbonate and stirred at room temperature overnight. After work up by extraction with water, the CBZ protected amine product was further purified by precipitation from toluene/hexane.

The CBZ protected amine product was then reacted with 3 equivalents of potassium t-butoxide in THF at 0 C to yield compounds 117 and 118 which were separated by silica gel column chromatography.

Examples 89 and 90

Preparation of 121 or 122

Compound 118 (.013 moles, 6.79 g) is dissolved in 135 ml of dry chloroform and cooled to -78° C., next 1.85 ml of boron tribromide (4.9 g) was added and the reaction is allowed to warm to room temperature. Reaction is complete after 1.5 hours. The reaction is quenched by addition of 10% potassium carbonate at 0 C. and extract with ether. Removal of ether yields compound 121. A similar procedure can be used to produce 122 from 117.

Examples 93-96

Compounds 126, 127, 128 and 129 as set forth in Table 3 were prepared substantially in the manner described above for compounds 115, 116, 111 and 113, respectively, except that fluorobenzene was used as a starting material in place of anisole.

                                      TABLE 3                                      __________________________________________________________________________     Specific Compounds (#102-111, 113-130, 132-134,                                136, 138, 142-144, 262-296)                                                     ##STR406##                                                                    Cp#                                                                               R.sup.1                                                                             R.sup.2                                                                             R.sup.3                                                                            R.sup.4                                                                            R.sup.5    R.sup.6                                                                               (R.sup.x)q                              __________________________________________________________________________     102                                                                               Et-  n-Bu-                                                                               HO--                                                                               H-- Ph-       H--     I.sup.-, 7-(CH.sub.3).sub.3                                                    N.sup.+ --                              103                                                                               n-Bu-                                                                               Et-  HO--                                                                               H-- Ph-       H--     I.sup.-, 7-(CH.sub.3).sub.3                                                    N.sup.+ --                              104                                                                               Et-  n-Bu-                                                                               HO--                                                                               H-- Ph-       H--     7-(CH.sub.3).sub.2 N--                  105                                                                               Et-  n-Bu-                                                                               HO--                                                                               H-- Ph-       H--     7-CH.sub.3 SO.sub.2 NH--                106                                                                               Et-  n-Bu-                                                                               HO--                                                                               H-- Ph-       H--     7-Br--CH.sub.2 --CONH--                 107                                                                               n-Bu-                                                                               Et-  HO--                                                                               H-- p-n-C.sub.10 H.sub.21 --O-Ph-                                                             H--    7-NH.sub.2 --                           108                                                                               Et-  n-Bu-                                                                               HO--                                                                               H-- Ph-       H--     7-C.sub.5 H.sub.11 CONH--               109                                                                               Et-  n-Bu-                                                                               HO--                                                                               H-- p-n-C.sub.10 H.sub.21 --O-Ph-                                                             H--    7-NH.sub.2 --                           110                                                                               Et-  n-Bu-                                                                               HO--                                                                               H-- Ph-       H--     7-CH.sub.3 CONH--                       111                                                                               n-Bu-                                                                               Et-  HO--                                                                               H-- p-HO-Ph-  H--     7-NH.sub.2 --                           113                                                                               Et-  n-Bu-                                                                               HO--                                                                               H-- p-HO-Ph-  H--     7-NH.sub.2 --                           114                                                                               Et-  n-Bu-                                                                               HO--                                                                               H-- p-CH.sub.3 O-Ph-                                                                         H--     7-NH.sub.2 --                           115                                                                               n-Bu-                                                                               Et-  HO--                                                                               H-- p-CH.sub.3 O-Ph-                                                                         H--     7-NH--CBZ                               116                                                                               Et-  n-Bu-                                                                               HO--                                                                               H-- p-CH.sub.3 O-Ph-                                                                         H--     7-NH--CBZ                               117                                                                               n-Bu-                                                                               Et-  HO--                                                                               H-- Ph-       H--     7-NH--CBZ                               118                                                                               Et-  n-Bu-                                                                               HO--                                                                               H-- Ph-       H--     7-NH--CBZ                               119                                                                               Et-  n-Bu-                                                                               HO--                                                                               H-- Ph-       H--     7-NHCO.sub.2 -t-Bu                      120                                                                               n-Bu-                                                                               Et-  HO--                                                                               H-- Ph-       H--     7-NHCO.sub.2 -t-Bu                      121                                                                               Et-  n-Bu-                                                                               HO--                                                                               H-- Ph-       H--     7-NH.sub.2 --                           122                                                                               n-Bu-                                                                               Et-  HO--                                                                               H-- Ph-       H--     7-NH.sub.2 --                           123                                                                               Et-  n-Bu-                                                                               HO--                                                                               H-- Ph-       H--     7-n-C.sub.6 H.sub.13 --NH--             124                                                                               n-Bu-                                                                               Et-  HO--                                                                               H-- Ph-       H--     7-n-C.sub.6 H.sub.13 --NH--             125                                                                               Et-  n-Bu-                                                                               HO--                                                                               H-- Ph-       H--     I.sup.-, 8-(CH.sub.3).sub.3)N.sup.+                                             (CH.sub.2 CH.sub.2 O).sub.3 --         126                                                                               n-Bu-                                                                               Et-  HO--                                                                               H-- p-F-Ph-   H--     7-NH--CBZ                               127                                                                               n-Bu-                                                                               Et-  HO--                                                                               H-- p-F-Ph-   H--     7-NH.sub.2 --                           128                                                                               Et-  n-Bu-                                                                               HO--                                                                               H-- p-F-Ph-   H--     7-NH--CBZ                               129                                                                               Et-  n-Bu-                                                                               HO--                                                                               H-- p-F-Ph-   H--     7-NH.sub.2 --                           130                                                                               Et-  n-Bu-                                                                               HO--                                                                               H-- Ph-       H--     I.sup.-, 8-(CH.sub.3).sub.3                                                    N.sup.+ C.sub.6 H.sub.12 O--            132                                                                               Et-  n-Bu-                                                                               HO--                                                                               H-- Ph-       H--     8-phthal-imidyl-C.sub.6 H.sub.12                                               O--                                     133                                                                               Et-  n-Bu-                                                                               HO--                                                                               H-- Ph-       H--     8-n-C.sub.10 H.sub.21 --                134                                                                               Et-  n-Bu-                                                                               HO--                                                                               H-- Ph-       H--     8-I--(C.sub.2 H.sub.4 O).sub.3 --       136                                                                               Et-  n-Bu-                                                                               HO--                                                                               H-- Ph-       H--     8-HO--                                  138                                                                               n-Bu-                                                                               Et-  HO--                                                                               H-- Ph-       H--     8-CH.sub.3 CO.sub.2 --                  142                                                                               Et-  n-Bu-                                                                               H-- HO--                                                                               H--       m-CH.sub.3 O-Ph-                                                                       7-CH.sub.3 S--                          143                                                                               Et-  n-Bu-                                                                               HO--                                                                               H-- m-CH.sub.3 O-Ph-                                                                         H--     7-CH.sub.3 S--                          144                                                                               Et-  n-Bu-                                                                               HO--                                                                               H-- p-F-Ph-   H--     7-(N)-azetidine                         262                                                                               Et-  n-Bu-                                                                               HO--                                                                               H-- m-CH.sub.3 O-Ph-                                                                         H--     7-CH.sub.3 O--                          263                                                                               Et-  n-Bu-                                                                               H-- HO--                                                                               H--       m-CH.sub.3 O-Ph-                                                                       7-CH.sub.3 O--                          264                                                                               Et-  n-Bu-                                                                               HO--                                                                               H-- m-CF.sub.3 -Ph-                                                                          H--     7-CH.sub.3 O--                          265                                                                               Et-  n-Bu-                                                                               H-- HO--                                                                               H--       m-CF.sub.3 -Ph-                                                                        7-CH.sub.3 O--                          266                                                                               Et-  n-Bu-                                                                               HO--                                                                               H-- m-HO-Ph-  H--     7-HO--                                  267                                                                               Et-  n-Bu-                                                                               HO--                                                                               H-- m-HO-Ph-  H--     7-CH.sub.3 O--                          268                                                                               Et-  n-Bu-                                                                               HO--                                                                               H-- p-F-Ph-   H--     7-CH.sub.3 O--                          269                                                                               Et-  n-Bu-                                                                               H-- HO--                                                                               H--       p-F-Ph- 7-CH.sub.3 O--                          270                                                                               Et-  n-Bu-                                                                               HO--                                                                               H-- p-F-Ph-   H--     7-HO--                                  271                                                                               Et-  n-Bu-                                                                               HO--                                                                               H-- m-CH.sub.3 O-Ph-                                                                         H--     7-Br--                                  272                                                                               Et-  n-Bu-                                                                               H-- HO--                                                                               H--       m-CH.sub.3 O-Ph-                                                                       7-Br--                                  273                                                                               Et-  n-Bu-                                                                               H-- HO--                                                                               H--       p-F-Ph- 7-F--                                   274                                                                               Et-  n-Bu-                                                                               HO--                                                                               H-- p-F-Ph-   H--     7-F--                                   275                                                                               Et-  n-Bu-                                                                               H-- HO--                                                                               H--       m-CH.sub.3 O-Ph-                                                                       7-F--                                   276                                                                               Et-  n-Bu-                                                                               HO--                                                                               H-- m-CH.sub.3 O-Ph-                                                                         H--     7-F--                                   277                                                                               Et-  n-Bu-                                                                               HO--                                                                               H-- m-F-Ph-   H--     7-CH.sub.3 O--                          278                                                                               Et-  n-Bu-                                                                               H-- HO--                                                                               H--       o-F-Ph- 7-CH.sub.3 O--                          279                                                                               Et-  n-Bu-                                                                               H-- HO--                                                                               H--       m-F-Ph- 7-CH.sub.3 O--                          280                                                                               Et-  n-Bu-                                                                               HO--                                                                               H-- o-F-Ph-   H--     7-CH.sub.3 O--                          281                                                                               Et-  n-Bu-                                                                               HO--                                                                               H-- p-F-Ph-   H--     7-CH.sub.3 S--                          282                                                                               Et-  n-Bu-                                                                               HO--                                                                               H-- p-F-Ph-   H--     7-CH.sub.3 -                            283                                                                               Et-  n-Bu-                                                                               H-- HO--                                                                               H--       p-F-Ph- 7-CH.sub.3 -                            284                                                                               Et-  n-Bu-                                                                               HO--                                                                               H-- p-F-Ph-   H--     7-(N)-morpholine                        285                                                                               Et-  n-Bu-                                                                               HO--                                                                               H-- p-F-Ph-   H--     7-(N)-pyrrolidine                       286                                                                               Et-  Et-  HO--                                                                               H-- Ph-       H--     7-NH--CBZ--                             287                                                                               Et-  Et-  HO--                                                                               H-- Ph-       H--     7-NH.sub.2 --                           288                                                                               CH.sub.3 --                                                                         CH.sub.3 --                                                                         HO--                                                                               H-- Ph-       H--     7-NH.sub.2 --                           289                                                                               n-C.sub.3 H.sub.7 --                                                                n-C.sub.3 H.sub.7 --                                                                HO--                                                                               H-- Ph-       H--     7-NH.sub.2 --                           290                                                                               n-Bu-                                                                               n-Bu-                                                                               HO--                                                                               H-- Ph-       H--     7-NH.sub.2 --                           291                                                                               n-Bu-                                                                               n-Bu-                                                                               HO--                                                                               H-- Ph-       H--     7-NH--CBZ--                             292                                                                               n-Bu-                                                                               n-Bu-                                                                               HO--                                                                               H-- p-F-Ph-   H--     7-NH.sub.2 --                           293                                                                               n-Bu-                                                                               n-Bu-                                                                               HO--                                                                               H-- Ph-       H--     7-PhCH.sub.2 N--                        294                                                                               n-Bu-                                                                               n-Bu-                                                                               HO--                                                                               H-- Ph-       H--     7-(CH.sub.3).sub.2 N--                  295                                                                               Et-  n-Bu-                                                                               HO--                                                                               H-- p-I--(C.sub.2 H.sub.4 O).sub.3 -Ph-                                                      H--     7-NH.sub.2 --                           296                                                                               Et-  n-Bu-                                                                               HO--                                                                               H-- I.sup.-, p-                                                                              H--     7-NH.sub.2 --                                                (CH.sub.3).sub.3 N.sup.+ (C.sub.2 H.sub.4 O).sub.3                             -Ph-                                                      __________________________________________________________________________

                                      TABLE 3A                                     __________________________________________________________________________     Bridged Benzothiepines (#101, 112, 131, 135, 137, 139-141)                     __________________________________________________________________________      ##STR407##                                                                    CPD #101 (Example 59)                                                           ##STR408##                                                                    CPD #112 (Example 53)                                                           ##STR409##                                                                    CPD #113 (Example 56)                                                           ##STR410##                                                                    CPD #135 (Example 55)                                                           ##STR411##                                                                    CPD #137 (Example 57)                                                           ##STR412##                                                                    CPD #139 (Example 58)                                                           ##STR413##                                                                    CPD #140 (Example 51)                                                           ##STR414##                                                                    CPD #141 (Example 50)                                                          __________________________________________________________________________

Examples 104-231

Using in each instance a method generally described in those of Examples 1 to 72 appropriate to the substituents to be introduced, including where necessary other common synthesis expedients well known to the art, compounds are prepared having the structures set forth in Table 4. The starting materials illustrated in the reaction schemes shown above are varied in accordance with principles of organic synthesis well known to the art in order to introduce the indicated substituents in the 4- and 5-positions (R³, R⁴, R⁵, R⁶) and in the indicated position on the benzo ring (R^(x)).

                  TABLE 4                                                          ______________________________________                                         Alternative compounds #1 (#302-312, 314-430)                                    ##STR415##                                                                    Cpd #      R.sup.5      (R.sup.x)q                                             ______________________________________                                         302        p-F-Ph-      7-(1-aziridine)                                        303        p-F-Ph-      7-EtS--                                                304        p-F-Ph-      7-CH.sub.3 S(O)--                                      305        p-F-Ph-      7-CH.sub.3 S(O).sub.2 --                               306        p-F-Ph-      7-PhS--                                                307        p-F-Ph-      7-CH.sub.3 S--                                                                 9-CH.sub.3 S--                                         308        p-F-Ph-      7-CH.sub.3 O--                                                                 9-CH.sub.3 O--                                         309        p-F-Ph-      7-Et-                                                  310        p-F-Ph-      7-iPr-                                                 311        p-F-Ph-      7-t-Bu-                                                312        p-F-Ph-      7-(1-pyrazole)-                                        314        m-CH.sub.3 O-Ph                                                                             7-(1-azetidine)                                        315        m-CH.sub.3 O-Ph-                                                                            7-(1-aziridine)                                        316        m-CH.sub.3 O-Ph-                                                                            7-EtS--                                                317        m-CH.sub.3 O-Ph-                                                                            7-CH.sub.3 S(O)--                                      318        m-CH.sub.3 O-Ph-                                                                            7-CH.sub.3 S(O).sub.2 --                               319        m-CH.sub.3 O-Ph-                                                                            7-PhS--                                                320        m-CH.sub.3 O-Ph                                                                             7-CH.sub.3 S--                                                                 9-CH.sub.3 S--                                         321        m-CH.sub.3 O-Ph                                                                             7-CH.sub.3 O--                                                                 9-CH.sub.3 O--                                         322        m-CH.sub.3 O-Ph                                                                             7-Et-                                                  323        m-CH.sub.3 O-Ph                                                                             7-iPr-                                                 324        m-CH.sub.3 O-Ph                                                                             7-t-Bu-                                                325        p-F-Ph-      6-CH.sub.3 O--                                                                 7-CH.sub.3 O--                                                                 8-CH.sub.3 O--                                         326        p-F-Ph-      7-(1-azetidine)                                                                9-CH.sub.3 --                                          327        p-F-Ph-      7-EtS--                                                                        9-CH.sub.3 --                                          328        p-F-Ph-      7-CH.sub.3 S(O)--                                                              9-CH.sub.3 --                                          329        p-F-Ph-      7-CH.sub.3 S(O).sub.2 --                                                       9-CH.sub.3 --                                          330        p-F-Ph-      7-PhS--                                                                        9-CH.sub.3 --                                          331        p-F-Ph-      7-CH.sub.3 S--                                                                 9-CH.sub.3 --                                          332        p-F-Ph-      7-CH.sub.3 O--                                                                 9-CH.sub.3 --                                          333        p-F-Ph-      7-CH.sub.3 --                                                                  9-CH.sub.3 --                                          334        p-F-Ph-      7-CH.sub.3 O--                                                                 9-CH.sub.3 O--                                         335        p-F-Ph-      7-(1-pyrrole)                                          336        p-F-Ph-      7-(N)N'-methylpiperazine                               337        p-F-Ph-      Ph-                                                    338        p-F-Ph-      7-CH.sub.3 C(═CH.sub.2)--                          339        p-F-Ph-      7-cyclpropyl                                           340        p-F-Ph-      7-(CH.sub.3).sub.2 NHN--                               341        p-F-Ph-      7-(N)-azetidine                                                                9-CH.sub.3 S--                                         342        p-F-Ph-      7-(N-pyrrolidine)                                                              9-CH.sub.3 S--                                         343        p-F-Ph-      7-(CH.sub.3).sub.2 N--                                                         9-CH.sub.3 S--                                         344        m-CH.sub.3 O-Ph-                                                                            7-(1-pyrazole)                                         345        m-CH.sub.3 O-Ph-                                                                            7-(N)N'-methylpiperazine                               346        m-CH.sub.3 O-Ph-                                                                            Ph-                                                    347        m-CH.sub.3 O-Ph-                                                                            7-CH.sub.3 C(═CH.sub.2)--                          348        m-CH.sub.3 O-Ph-                                                                            7-cyclopropyl                                          349        m-CH.sub.3 O-Ph-                                                                            7-(CH.sub.3).sub.2 NHN--                               350        m-CH.sub.3 O-Ph-                                                                            7-(N)-azetidine                                                                9-CH.sub.3 S--                                         351        m-CH.sub.3 O-Ph-                                                                            7-(N-pyrrolidine)-                                                             9-CH.sub.3 S--                                         352        m-CH.sub.3 O-Ph-                                                                            7-(CH.sub.3).sub.2 N--                                                         9-CH.sub.3 S--                                         353        m-CH.sub.3 O-Ph-                                                                            6-CH.sub.3 O--                                                                 7-CH.sub.3 O--                                                                 8-CH.sub.3 O--                                         354        m-CH.sub.3 O-Ph-                                                                            7-(1-azetidine)                                                                9-CH.sub.3 --                                          355        m-CH.sub.3 O-Ph-                                                                            7-EtS--                                                                        9-CH.sub.3 --                                          356        m-CH.sub.3 O-Ph-                                                                            7-CH.sub.3 S(O)--                                                              9-CH.sub.3 --                                          357        m-CH.sub.3 O-Ph-                                                                            7-CH.sub.3 S(O).sub.2 --                                                       9-CH.sub.3 --                                          358        m-CH.sub.3 O-Ph-                                                                            7-PhS--                                                                        9-CH.sub.3 --                                          359        m-CH.sub.3 O-Ph-                                                                            7-CH.sub.3 S--                                                                 9-CH.sub.3 --                                          360        m-CH.sub.3 O-Ph-                                                                            7-CH.sub.3 O--                                                                 9-CH.sub.3 --                                          361        m-CH.sub.3 O-Ph-                                                                            7-CH.sub.3 --                                                                  9-CH.sub.3 --                                          362        m-CH.sub.3 O-Ph-                                                                            7-CH.sub.3 O--                                                                 9-CH.sub.3 O--                                         363        thien-2-yl   7-(1-aziridine)                                        364        thien-2-yl   7-EtS--                                                365        thien-2-yl   7-CH.sub.3 S(O)--                                      366        thien-2-yl   7-CH.sub.3 S(O).sub.2 --                               367        thien-2-yl   7-PhS--                                                368        thien-2-yl   7-CH.sub.3 S--                                                                 9-CH.sub.3 S--                                         369        thien-2-yl   7-CH.sub.3 O--                                                                 9-CH.sub.3 O--                                         370        thien-2-yl   7-Et-                                                  371        thien-2-yl   7-iPr-                                                 372        thien-2-yl   7-t-Bu-                                                373        thien-2-yl   7-(1-pyrrole)-                                         374        thien-2-yl   7-CH.sub.3 O--                                         375        thien-2-yl   7-CH.sub.3 S--                                         376        thien-2-yl   7-(1-azetidine)                                        377        thien-2-yl   7-Me-                                                  378        5-Cl-thien-2-yl                                                                             7-(1-azetidine)                                        379        5-Cl-thien-2-yl                                                                             7-(1-aziridine)                                        380        5-Cl-thien-2-yl                                                                             7-EtS--                                                381        5-Cl-thien-2-yl                                                                             7-CH.sub.3 S(O)--                                      382        5-Cl-thien-2-yl                                                                             7-CH.sub.3 S(O).sub.2 --                               383        5-Cl-thien-2-yl                                                                             7-PhS--                                                384        5-Cl-thien-2-yl                                                                             7-CH.sub.3 S--                                                                 9-CH.sub.3 S--                                         385        5-Cl-thien-2-yl                                                                             7-CH.sub.3 O--                                                                 9-CH.sub.3 O--                                         386        5-Cl-thien-2-yl                                                                             7-Et-                                                  387        5-Cl-thien-2-yl                                                                             7-iPr-                                                 388        5-Cl-thien-2-yl                                                                             7-t-Bu-                                                389        5-Cl-thien-2-yl                                                                             7-CH.sub.3 O--                                         390        5-Cl-thien-2-yl                                                                             7-CH.sub.3 S--                                         391        5-Cl-thien-2-yl                                                                             7-Me                                                   392        thien-2-yl   7-(1-azetidine)                                                                9-CH.sub.3 --                                          393        thien-2-yl   7-EtS--                                                                        9-CH.sub.3 --                                          394        thien-2-yl   7-CH.sub.3 S(O)--                                                              9-CH.sub.3 --                                          395        thien-2-yl   7-CH.sub.3 S(O).sub.2 --                                                       9-CH.sub.3 --                                          396        thien-2-yl   7-PhS--                                                                        9-CH.sub.3 --                                          397        thien-2-yl   7-CH.sub.3 S--                                                                 9-CH.sub.3 --                                          398        thien-2-yl   7-CH.sub.3 O--                                                                 9-CH.sub.3 --                                          399        thien-2-yl   7-CH.sub.3 --                                                                  9-CH.sub.3 --                                          400        thien-2-yl   7-CH.sub.3 O--                                                                 9-CH.sub.3 O--                                         401        thien-2-yl   7-(1-pyrazrole)                                        402        thien-2-yl   7-(N)N'-methylpiperazine                               403        thien-2-yl   Ph-                                                    404        thien-2-yl   7-CH.sub.3 C(═CH.sub.2)--                          405        thien-2-yl   7-cyclpropyl                                           406        thien-2-yl   7-(CH.sub.3).sub.2 NHN--                               407        thien-2-yl   7-(N)-azetidine                                                                9-CH.sub.3 S--                                         408        thien-2-yl   7-(N-pyrrolidine)                                                              9-CH.sub.3 S--                                         409        thien-2-yl   7-(CH.sub.3).sub.2 N--                                                         9-CH.sub.3 S--                                         411        5-Cl-thien-2-yl                                                                             7-(1-pyrazrole)                                        412        5-Cl-thien-2-yl                                                                             7-(N)N'-methylpiperazine                               413        5-Cl-thien-2-yl                                                                             Ph-                                                    414        5-Cl-thien-2-yl                                                                             7-CH.sub.3 C(═CH.sub.2)--                          415        5-Cl-thien-2-yl                                                                             7-cyclopropyl                                          416        5-Cl-thien-2-yl                                                                             7-(CH.sub.3).sub.2 NHN--                               417        5-Cl-thien-2-yl                                                                             7-(N)-azetidine                                                                9-CH.sub.3 S--                                         418        5-Cl-thien-2-yl                                                                             7-(N-pyrrolidine)-                                                             9-CH.sub.3 S--                                         419        5-Cl-thien-2-yl                                                                             7-(CH.sub.3).sub.2 N--                                                         9-CH.sub.3 S--                                         420        5-Cl-thien-2-yl                                                                             7-(1-azetidine)                                                                9-CH.sub.3 --                                          421        5-Cl-thien-2-yl                                                                             7-EtS--                                                                        9-CH.sub.3 --                                          422        5-Cl-thien-2-yl                                                                             7-CH.sub.3 S(O)--                                                              9-CH.sub.3 --                                          423        5-Cl-thien-2-yl                                                                             7-CH.sub.3 S(O).sub.2 --                                                       9-CH.sub.3 --                                          424        5-Cl-thien-2-yl                                                                             7-PhS--                                                                        9-CH.sub.3 --                                          425        5-Cl-thien-2-yl                                                                             7-CH.sub.3 S--                                                                 9-CH.sub.3 --                                          426        5-Cl-thien-2-yl                                                                             7-CH.sub.3 O--                                                                 9-CH.sub.3 --                                          427        5-Cl-thien-2-yl                                                                             7-CH.sub.3 --                                                                  9-CH.sub.3 --                                          428        5-Cl-thien-2-yl                                                                             7-CH.sub.3 O--                                                                 9-CH.sub.3 O--                                         429        thien-2-yl   6-CH.sub.3 O--                                                                 7-CH.sub.3 O--                                                                 8-CH.sub.3 O--                                         430        5-Cl-thien-2-yl                                                                             6-CH.sub.3 O--                                                                 7 -CH.sub.3 O--                                                                8 -CH.sub.3 O--                                        ______________________________________                                    

Examples 232-1394

Using in each instance a method generally described in those of Examples 1 to 72 appropriate to the substituents to be introduced, including where necessary other common synthesis expedients well known to the art, compounds are prepared having the structures set forth in Table 1. The starting materials illustrated in the reaction schemes shown above are varied in accordance with principles of organic synthesis well known to the art in order to introduce the indicated substituents in the 4- and 5-positions (R³, R⁴, R⁵, R⁶) and in the indicated position on the benzo ring (R^(x)).

Example 1395 Dibutyl 4-fluorobenzene dialdehyde ##STR416## Step 1: Preparation of dibutyl 4-fluoro benzene dialdehyde

To a stirred solution of 17.5 g (123 mmol) of 2,5-difluorobenzaldehyde (Aldrich) in 615 mL of DMSO at ambient temperature was added 6.2 g (135 mmol) of lithium sulfide (Aldrich). The dark red solution was stirred at 75 C. for 1.5 hours, or until the starting material was completely consumed, and then 34 g (135 mmol) of dibutyl mesylate aldehyde was added at about 50 C. The reaction mixture was stirred at 75 C. for three hours or until the reaction was completed. The cooled solution was poured into water and extracted with ethyl acetate. The combined extracts were washed with water several times, dried (MgSO₄) and concentrated in vacuo. Silica gel chromatographic purification of the crude product gave 23.6 g (59%) of fluorobenzene dialdehyde as a yellow oil: ¹ H NMR (CDCl₃) d 0.87 (t, J=7.05 Hz, 6H), 1.0-1.4 (m, 8H), 1.5-1.78 (m, 4H), 3.09 (s, 2H), 7.2-7.35 (m, 1H), 7.5-7.6 (m, 2H), 9.43 (s, 1H), 10.50 (d, J=2.62 Hz, 1H).

Step 2: Preparation of dibutyl 4-fluorobenzyl alcohol

To a solution of 22.6 g (69.8 mmol) of the dialdehyde obtained from Step 1 in 650 mL of THF at -60 C. was added 69.8 mL (69.8 mmol) of DIBAL (1M in THF) via a syringe. The reaction mixture was stirred at -40 C. for 20 hours. To the cooled solution at -40 C. was added sufficient amount of ethyl acetate to quench the excess of DIBAL, followed by 3 N HCl. The mixture was extracted with ethyl acetate, washed with water, dried (MgSO₄), and concentrated in vacuo. Silica gel chromatographic purification of the crude product gave 13.5 g (58%) of recovered starting material, and 8.1 g (36%) of the desired fluorobenzyl alcohol as a colorless oil: ¹ H NMR (CDCl₃) d 0.88 (t, J=7.05 Hz, 6H), 1.0-1.4 (m, 8H), 1.5-1.72 (m, 4H), 1.94 (br s, 1H), 3.03 (s, 2H), 4.79 (s, 2H), 6.96 (dt, J=8.46, 3.02 Hz, 1H), 7.20 (dd, J=9.47, 2.82 Hz, 1H), 7.42 (dd, J=8.67, 5.64, 1H), 9.40 (s, 1H).

Step 3: Preparation of dibutyl 4-fluorobenzyl bromide

To a solution of 8.1 g (25 mmol) of benzyl alcohol obtained from Step 2 in 100 mL of DMF at -40 C. was added 47 g (50 mmol) of bromotriphenyphosphonium bromide (Aldrich). The resulting solution was stirred cold for 30 min, then was allowed to warm to 0° C. To the mixture was added 10% solution of sodium sulfite and ethyl acetate. The extract was washed a few times with water, dried (MgSO₄), and concentrated in vacuo. The mixture was stirred in small amount of ethyl acetate/hexane mixture (1:4 ratio) and filtered through a pad of silica gel, eluting with same solvent mixture. The combined filtrate was concentrated in vacuo to give 9.5 g (98%) of the desired product as a colorless oil: ¹ H NMR (CDCl₃) d 0.88 (t, J=7.05 Hz, 6H), 1.0-1.4 (m, 8H), 1.55-1.78 (m, 4H), 3.11 (s, 2H), 4.67 (s, 2H), 7.02 (dt, J=8.46, 3.02 Hz, 1H), 7.15 (dd, J=9.47, 2.82 Hz, 1H), 7.46 (dd, J=8.67, 5.64, 1H), 9.45 (s, 1H).

Step 4: Preparation of sulfonyl 4-fluorobenzyl bromide

To a solution of 8.5 g (25 mmol) of sulfide obtained from Step 3 in 200 mL of CH₂ Cl₂ at 0° C. was added 15.9 g (60 mmol) of mCPBA (64% peracid). The resulting solution was stirred cold for 10 min, then was allowed to stirred ambient temperature for 5 hours. To the mixture was added 10% solution of sodium sulfite and ethyl acetate. The extract was washed several times with saturated Na₂ CO₃, dried (MgSO₄), and concentrated in vacuo to give 10.2 g (98%) of the desired product as a colorless oil: ¹ H NMR (CDCl₃) d 0.91 (t, J=7.05 Hz, 6H), 1.03-1.4 (m, 8H), 1.65-1.82 (m, 2H), 1.90-2.05 (m, 2H), 3.54 (s, 2H), 5.01 (s, 2H), 7.04-7.23 (m, 1H), 7.30 (dd, J=8.87, 2.42 Hz, 1H), 8.03 (dd, J=8.86, 5.64, 1H), 9.49 (s, 1H).

Example 1396 ##STR417##

Generic Scheme X: The nucleophilic substitution of an appropriately substituted 2-fluorobenzaldehyde with lithium sulfide or other nucleophilic sulfide anion in polar solvent (such as DMF, DMA, DMSO ..etc), followed by the addition of dialkyl mesylate aldehyde (X), provided a dialkyl benzene dialdehyde Y. DIBAL reduction of the dialdehyde at low temperature yielded benzyl alcohol monoaldehyde Z. Conversion of benzyl alcohol to benzyl bromide, followed by oxidation of sulfide to sulfone yielded the key intermediate W.

Preparation of N-propylsulfonic acid

To a solution of 51 mg (111 μm) Compound X in ethanol (400 μl) was added 1,3 propane sultone (19.5 μl, 222 μm). The reaction was stirred in a sealed vial at 55° C. for 25 hr. Sample was concentrated under a nitrogen stream and purified by reversed phase chromatography using acetonitrile/water as eluent (30-45%) and afforded the desired material as an off-white solid (28.4 mg, 44%): ¹ H NMR (CDCL₃) d 0.82-0.96 (m, 6H), 1.11-1.52 (m of m, 10H), 1.58-1.72 (m, 1H), 2.08-2.21 (m, 1H), 2.36-2.50 (m, 2H), 2.93 (s, 6H), 3.02-3.22 (m of m, 5H), 3.58-3.76 (m, 2H), 4.15 (s, 1H), 5.51 (s, 1H), 6.45-6.58 (m, 1H), 6.92-7.02 (m, 1H), 7.35-7.41 (m, 1H), 7.41-7.51 (m, 2H), 8.08 (d, J=8.1 Hz, 1H), 8.12-8.25 (m, 1H); MS ES- M-H m/z 579.

Example 1397

The 7-fluoro, 9-fluoro and 7,9-difluoro analogs of benzothiepine compounds of this invention can be reacted with sulfur and nitrogen nucleophiles to give the corresponding sulfur and nitrogen substituted analogs. The following example demonstrates the synthesis of these analogs.

3,3-Dibutyl-5a-(4'-fluorophenyl)-4a-hydroxy-7-methylthio-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide. ##STR418##

A mixture of 0.4 g of 3,3-dibutyl-7-fluoro-5a-(4'-fluorophenyl)-4a-hydroxy-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide, prepared by previously described method, 0.12 g of sodium methanethiolate and 20 ml of DMF was stirred at 50 C. for 3 days. An additional 0.1 g of sodium methanethiolate was added to the reaction mixture and the mixture was stirred for additional 20 h at 50 C. then was concentrated in vacuo. The residue was triturated with water and extracte with ether. The ether extract was dried over MgSO₄ and concentrated in vacuo to 0.44 g of an oil. Purification by HPLC (10% EtOAc in hexane) gave 0.26 g of needles, mp 164-165.5%C.

3,3-Dibutyl-9-dimethylamino-7-fluoro-5a-(4'-fluorophenyl)-4a-hydroxy-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide and 7,9-Bis(dimethylamino)-3,3-dibutyl-5a-(4'-fluorophenyl)-4a-hydroxy-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide ##STR419##

A solution of 0.105 g of 3,3-dibutyl-7,9-difluoro-5a-(4'-fluorophenyl)-4a-hydroxy-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide, prepared by the method described previously, in 20 ml of 2 N dimethylamine in THF was heated at 160 C. in a sealed Parr reactor overnight. The reaction mixture was cooled and concentrated in vacuo. The residue was triturated with 25 ml of water and extracted with ether. The ether extract was dried over MgSO₄ and concentrated in vacuo. The residue was purified by HPLC (10% EtOAc in hexane) to give 35 mg of an earlier fraction which was identified as 3,3-dibutyl-9-dimethylamino-7-fluoro-5a-(4'-fluorophenyl)-4a-hydroxy-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide, MS (CI) m/e 480 (M⁺ +1), and 29 mg of a later fraction which was identified as 7,9-bis(dimethylamino)-3,3-dibutyl-5a-(4'-fluorophenyl)-4a-hydroxy-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide, MS (CI) m/e 505 (M⁺ +1).

The compounds of this invention can also be synthesized using cyclic sulfate (XL, below) as the reagent as shown in the following schemes XI and XII.

The following examples describe a procedure for using the cyclic sulfate as the reagent. ##STR420##

Scheme XI illustrates yet another route to benzothiepine-1,1-dioxides, particularly 3,3-dialkyl analogs, starting from the thiophenol XVIIIA. Thiophenol XVIIIA can be reacted with cyclic sulfate XL to give the alcohol XLI which can be oxidized to yield the aldehyde XLII. Aldehyde XLII itself can be further oxidized to give the sulfone XLIII which can be cyclized to give a stereoisomeric mixture of benzothiepine XLIVa and XLIVb.

Thiophenol XVIIIA can be prepared according to Scheme 3 as previously discussed and has the following formula: ##STR421## wherein R⁵, R^(x) and q are as previously defined for the compounds of formula I. Cyclic sulfate XL can be prepared according to synthetic procedures known in the art and has the following formula: ##STR422## wherein R¹ and R² are as previously defined for the compounds of formula I. Preferably, R¹ and R² are alkyl; more preferably, they are selected from the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, and pentyl; and still more preferably, R¹ and R² are n-butyl.

In the process of Scheme XI, thiophenol XVIIIA is initially reacted with cyclic sulfate XL. This reaction preferably is conducted in an aprotic solvent such as methoxyethyl ether. While the reaction conditions such as temperature and time are not narrowly critical, the reaction preferably is allowed to proceed at about room temperature for about two hours. The reaction preferably employs an approximately stoichiometric ratio of the starting materials, with a slight excess of cyclic sulfate XL being preferred. Reaction time and yield can be improved by using about 1.01 to 1.3 equivalents of cyclic sulfate XL for each equivalent of thiophenol XVIIIA present. More preferably, this ratio is about 1.1 equivalents of cyclic sulfate XL for each equivalent of thiophenol XVIIIA present.

In the process of the invention, thiophenol XVIIIA also is treated with an abstracting agent. The abstracting agent can be added to the solvent containing thiophenol XVIIIA prior to, concurrently with, or after the addition of cyclic sulfate XL. Without being held to a particular theory, it is believed the abstracting agent removes the hydrogen atom from the mercaptan group attached to the benzene ring of thiophenol XVIIIA. The resulting sulfur anion of the thiophenol then reacts with cyclic sulfate XL to open the sulfate ring. The sulfur anion of the thiophenol then bonds with a terminal carbon atom of the open ring sulfate. The terminal group at the unbonded end of the open ring sulfate is the sulfate group.

The abstracting agent generally is a base having a pH greater than about 10. Preferably, the base is an alkali metal hydride such as sodium hydride, lithium hydride or potassium hydride; more preferably, the base is sodium hydride. A slight excess of abstracting agent is preferred relative to thiophenol XVIIIA. Reaction time and yield is improved by using about 1.0 to about 1.1 equivalents of abstracting agent for each equivalent of thiophenol XVIIIA present. More preferably, this ratio is about 1.1 equivalents of abstracting agent for each equivalent of thiophenol XVIIIA present.

The sulfate group of the intermediate product of the reaction of thiophenol XVIIIA with cyclic sulfate XL is then removed, preferably by hydrolysis, to yield alcohol XLI. Suitable hydrolyzing agents include mineral acids, particularly hydrochloric acid and sulfuric acid.

The several reactions involving thiophenol XVIIIA, cyclic sulfate XL, the abstracting agent and the hydrolyzing agent can take place in situ without the need for isolation of any of the intermediates produced.

Alcohol XLI is then isolated by conventional methods (for example, extraction with aqueous methyl salicylate) and oxidized using standard oxidizing agents to aldehyde XLII. Preferably, the oxidizing agent is sulfur trioxide or pyridinium chlorochromate, and more preferably, it is pyridinium chlorochromate. The reaction is conducted in a suitable organic solvent such as methylene chloride or chloroform.

Aldehyde XLII is then isolated by conventional methods and further oxidized using standard oxidizing agents to sulfone-aldehyde XLIII. Preferably, the oxidizing agent is metachloroperbenzoic acid.

Sulfone-aldehyde XLIII likewise is isolated by conventional methods and then cyclized to form the stereoisomeric benzothiepines XLIVa and XLIVb. The cyclizing agent preferably is a base having a pH between about 8 and about 9. More preferably, the base is an alkoxide base, and still more preferably, the base is potassium tert-butoxide.

The two oxidation steps of Scheme XI can be reversed without adversely affecting the overall reaction. Alcohol XLI can be oxidized first to yield a sulfone-alcohol which is then oxidized to yield a sulfone-aldehyde. ##STR423##

Scheme XII illustrates still another route to benzothiepine-1,1-dioxides, particularly 3,3-dialkyl analogs, starting from the halobenzene L. Halobenzene L can be reacted with cyclic sulfate XL disclosed above to give the alcohol LI which can be oxidized to yield the sulfone-alcohol LII. Sulfone-alcohol LII itself can be further oxidized to give the sulfone-aldehyde LIII which can be cyclized to give a stereoisomeric mixture of benzothiepine LIVa and LIVb.

Halobenzene L (which is commercially available or can be synthesized from commercially available halobenzenes by one skilled in the art) has the following formula: ##STR424## wherein R⁵, R^(x), and q are as previously defined for the compounds of formula I; R^(h) is a halogen such as chloro, bromo, fluoro or iodo; and R^(e) is an electron withdrawing group at the ortho or para position of the halobenzene, and is preferably a p-nitro or o-nitro group. Cyclic sulfate XL can be prepared as set forth in Scheme XI and can have the following formula: ##STR425## wherein R¹ and R² are as previously defined for the compounds of formula I. Preferably, R¹ and R² are alkyl; more preferably, they are selected from the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, and pentyl; and still more preferably, R¹ and R² are n-butyl.

In the process of Scheme XII, halobenzene L is initially reacted with cyclic sulfate XL. This reaction preferably is conducted in an aprotic solvent such as dimethyl formamide or N:N-dimethylacetamide, and more preferably, in dimethyl formamide. Although the reaction conditions such as temperature and time are not narrowly critical, the reaction preferably is allowed to proceed at between about 70° C. and about 90° C. for about 8 to 12 hours. More preferably, the reaction temperature is maintained at about 80° C. The reaction preferably employs an approximately stoichiometric ratio of the starting materials, with a slight excess of cyclic sulfate XL being preferred. Reaction time and yield is improved by using about 1.1 to 1.3 equivalents of cyclic sulfate XL for each equivalent of halobenzene L present. More preferably, this ratio is about 1.1 equivalents of cyclic sulfate XL for each equivalent of halobenzene L present.

In the process of the invention, halobenzene L also is treated with an abstracting agent. The abstracting agent can be added to the solvent containing halobenzene L prior to, concurrently with, or after the addition of cyclic sulfate XL. Without being held to a particular theory, it is believed the abstracting agent removes the halogen atom attached to the benzene ring of halobenzene L and replaces that atom with a divalent sulfur atom. The resulting sulfur anion reacts with cyclic sulfate XL to open the sulfate ring. The sulfur anion of the halobenzene then bonds with a terminal carbon atom of the open ring sulfate. The terminal group at the unbonded end of the open ring sulfate is the sulfate group. The abstracting agent generally is a dialkali metal sulfide, and preferably it is dilithium sulfide. A slight excess of the abstracting agent is preferred relative to halobenzene L. Reaction time and yield is improved by using about 1.01 to 1.3 equivalents of abstracting agent for each equivalent of halobenzene L present. More preferably, this ratio is about 1.05 equivalents of abstracting agent for each equivalent of halobenzene L present.

The sulfate group of the product of the reaction of thiophenol XVIIIA with cyclic sulfate XL is then removed, preferably by hydrolysis, to yield a mixture of an ester and alcohol LI. Suitable hydrolyzing agents include mineral acids, particularly hydrochloric acid and sulfuric acid. The ester is then converted to alcohol LI by treatment with an alkali metal hydroxide, preferably sodium hydroxide.

The several reactions involving halobenzene L, cyclic sulfate XL, the abstracting agent and the hydrolyzing agent can take place in situ without the need to isolate any of the intermediates produced.

Alcohol LI is then isolated by conventional methods (for example, extraction with aqueous methyl salicylate) and oxidized using standard oxidizing agents to sulfone-alcohol LII. Preferably, the oxidizing agent is metachloroperbenzoic acid. The reaction is conducted in a suitable organic solvent such as methylene chloride or chloroform.

Sulfone-alcohol LII is then isolated by conventional methods and further oxidized using standard oxidizing agents to sulfone-aldehyde LIII. Preferably, the oxidizing agent is sulfur trioxide or pyridinium chlorochromate, and more preferably, it is pyridinium chlorochromate. The reaction is conducted in a suitable organic solvent such as methylene chloride or chloroform.

Sulfone-aldehyde XLIII is then converted to the desired benzothiepine-1,1-dioxides according to the procedure previously set forth in Scheme XI.

The two oxidation steps can be reversed without adversely affecting the overall reaction. Alcohol XLI can be oxidized first to yield an aldehyde which is then oxidized to yield a sulfone-aldehyde.

Use of the cyclic sulfate reagent instead of a mesylate reagent in Schemes XI and XII improves the overall yield and avoids many of the purification difficulties encountered relative to those reaction schemes proceeding through a mesylate intermediate. Overall yields are significantly improved when a cyclic sulfate is used instead of a mesylate reagent. In addition, chromatographic separation of the intermediate product of the cyclic sulfate coupling step of the reaction is not necessary. For example, in Schemes XI and XII the intermediate is a water soluble alkali metal salt and the impurities can be removed by extraction with ether. The intermediate is then hydrolyzed to the desired alcohol.

Example Corresponding to Scheme XI

Step 1: Preparation of 2,2-dibutyl-1,3-propanediol ##STR426##

Lithium aluminum hydride (662 ml, 1.2 equivalents, 0.66 mol) in 662 mL of 1M THF was added dropwise to a stirred solution of dibutyl-diethylmalonate (150 g, 0.55 mol) (Aldrich) in dry THF (700 ml) while maintaining the temperature of the reaction mixture at between about -20° C. to about 0° C. using an acetone/dry ice bath. The reaction mixture was then stirred at room temperature overnight. The reaction was cooled to -20° C. and 40 ml of water, 80 ml of 10% NaOH and 80 ml of water were successively added dropwise. The resulting suspension was filtered. The filtrate was dried over sodium sulphate and concentrated under vacuum to give 98.4 g (yield 95%) of the diol as an oil. Proton NMR, carbon NMR and MS confirmed the product.

Step 2: Dibutyl-cyclic-sulfite ##STR427##

A solution of the dibutyl-diol of step 1 (103 g, 0.5478 mol) in anhydrous methylene chloride (500 ml) and triethylamine (221 g, 4 equivalents, 2.19 mol) was stirred at 0° C. under nitrogen. Thionyl chloride (97.78 g, 0.82 mol) was added dropwise to the mixture. Within 5 minutes the solution turned to yellow and then to black when the addition was completed within about half an hour. The reaction was completed within 3 hours (gas chromatography confirmed no starting material was left). The mixture was washed with ice water twice, and brine twice. The organic phase was dried over magnesium sulphate and concentrated under vacuum to give 128 g (yield 100%) of the dibutyl-cyclic-sulfite as a black oil. NMR and MS were consistent with the product.

Step 3: Dibutyl-cyclic sulfate ##STR428##

To a solution of the dibutyl-cyclic-sulfite of step 2 (127.5 g, 0.54 mol) in 600 ml acetonitrile and 500 ml of water cooled in an ice bath under nitrogen was added ruthenium(III) chloride (1 g) and sodium periodate (233 g, 1.08 mol). The reaction was stirred overnight and the color of the solution turned black. Gas chromatography confirmed there was no starting material left. The mixture was extracted once with 300 ml of ether and three times with brine. The organic phase was dried over magnesium sulphate and passed through celite. The filtrate was concentrated under vacuum and gave 133 g (yield 97.8%) of the dibutyl-cyclic-sulfate as an oil. Proton NMR, carbon NMR and MS confirmed the product.

Step 4: 2-[(2-4'-fluorobenzyl-4-methylphenylthio) methyl]-2-butylhexanol ##STR429##

A 60% oil dispersion of sodium hydride (0.27 g, 6.68 mmole) was washed with hexane. The hexane was decanted and 20 ml of methoxyethyl ether was added to the washed sodium hydride and cooled in an ice bath. A mixture of diphenylmethane thiophenol (1.55 g, 6.68 mmole) in 10 ml of methoxyethyl ether was added dropwise over a period of 15 minutes. A mixture of the dibutyl-cyclic-sulfate of step 3 (2.17 g, 8.66 mmole) in 10 ml of methoxyethyl ether was then added. The resulting mixture was stirred for 30 minutes at 0° C. and 1 hour at room temperature under nitrogen. Gas chromatography confirmed there was no thiol left. The solvent was evaporated and washed with water and ether two times. The water layer was separated and 20 ml of 10% NaOH was added. This aqueous mixture was boiled for 30 minutes, cooled, acidified with 6N HCI, and boiled for 10 minutes. The mixture was cooled and extracted with ether. The organic layer was washed successively with water and brine, dried over magnesium sulphate, and concentrated under vacuum to give 2.47 g (yield 92.5%) of the hexanol as an oil. Proton NMR, C13-NMR and MS confirmed the product.

Step 5: 2-[(2-4'-fluorobenzyl-4-methylphenylthio)methyl]-2-butylhexanal ##STR430##

To a solution of the hexanol of step 4 (2 g, 4.9 mmole) in 40 ml of methylene chloride cooled in an ice bath under nitrogen was added pyridinium chlorochromate (2.18 g, 9.9 mmole). The reaction mixture was stirred for 3 hours and filtered through silica gel. The filtrate was concentrated under vacuum to give 1.39 g (yield 70%) of the hexanal as an oil. Proton NMR, carbon NMR and MS confirmed the product.

Step 6: 2-[(2-4'-fluorobenzyl-4-methylphenylsulfonyl) methyl]-2-butylhexanal ##STR431##

To a solution of the hexanal of step 5 (0.44 g, 1.1 mmole) in 20 ml of methylene chloride cooled by an ice bath under nitrogen was added 70% metachloroperbenzoic acid (0.54 g, 2.2 mmole). The reaction mixture was stirred for 18 hours and filtered.

The filtrate was washed successively with 10% NaOH(3×), water, and brine, dried over magnesium sulphate, and concentrated under vacuum to give 0.42 g (yield 90%) of the hexanal as an oil. Proton NMR, carbon NMR and MS confirmed the product.

Step 7: Cis-3,3-dibutyl-7-methyl-5-(4'-fluoro-phenyl)-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide ##STR432##

A mixture of the hexanal of step 6 (0.37 g, 0.85 mmole) in 30 ml of anhydrous THF was stirred in an ice bath at a temperature of about 0° C. Potassium-tert-butoxide (102 mg, 0.85 mmole) was then added. After 3 hours thin layer chromatography confirmed the presence of the product and a small amount of the starting material. The crude reaction mixture was acidified with 10% HCl, extracted with ether, washed successively with water and brine, dried with MgSO₄, and concentrated under vacuum. This concentrate was purified by HPLC (10% EtOAc-Hexane). The first fraction came as 0.1 g of the starting material in the form of an oil. The second fraction yielded 0.27 g (75% yield) of the desired benzothiepine as a white solid. Proton NMR, carbon NMR and MS confirmed the product. (M+H=433).

Example Corresponding to Scheme XII

Step 1: 2-[(2-4'-methoxybenzyl-4-nitrophenylthio)methyl]-2-butylhexanol ##STR433##

Chlorodiphenylmethane (10 g) was dissolved in 25 ml of DMF and lithium sulfide [1.75 g, 1.05 equivalents] was added. The solution color changed to red. The reaction mixture was heated at 80° C. overnight. The solution was cooled to 0° C. and dibutyl-cyclic-sulfate (9.9 g; prepared as set forth in Step 3 of the Scheme XI examples) in 10 ml of DMF was added and stirred at room temperature overnight. The solvent was evaporated and washed successively with water and ether (three times). The water layer was separated and 40 ml of concentrated sulfuric acid was added and the reaction mixture boiled overnight. The mixture was cooled and extracted with ethyl acetate. The organic layer was washed successively with water and brine, dried over magnesium sulphate, and concentrated under vacuum. The product was boiled with 3M of NaOH for 1 hour. The mixture was cooled and extracted with ethyl acetate. The organic layer was washed successively with water and brine, dried over magnesium sulphate, and concentrated under vacuum. The concentrate was dissolved in methylene chloride, filtered through silica gel, eluted with 20% ethyl acetate and hexane, and concentrated under vacuum to give 11.9 g (yield 74%) of the hexanol as an oil. Proton NMR, C13-NMR and MS confirmed the product.

Step 2: 2-[2-4'-methoxybenzyl-4-nitrophenylthio)methyl]-2-butylhexanal ##STR434##

To a solution of the hexanol of step 1 (6 g, 13 mmole) in 50 ml methylene chloride cooled in ice bath under nitrogen was added 70% MCPBA (8.261 g, 33 mmole). The reaction was stirred for 18 hours at room temperature and filtered. The filtrate was washed successively with 10% NaOH (3×), water and brine, dried over magnesium sulphate, and concentrated under vacuum. The concentrate was dissolved in methylene chloride, filtered through silica gel, eluted with 20% ethyl acetate and hexane, and concentrated under vacuum to give 5 g (yield 77.7%) of the hexanal as a white solid, MP 58-60° C. Proton NMR, C13-NMR and MS confirmed the product.

Example 1398

Step 1. Preparation of 2 ##STR435##

To a solution of 6.0 g of dibutyl 4-fluorobenzene dialdehyde of Example 1395 (14.3 mmol) in 72 mL of toluene and 54 mL of ethanol was added 4.7 g 3-nitrobenzeneboronic acid (28.6 mmol), 0.8 g of tetrakis (triphenylphosphine) palladium(0) (0.7 mmol) and 45 mL of a 2 M solution of sodium carbonate in water. This heterogeneous mixture was refluxed for three hours, then cooled to ambient temperature and partitioned between ethyl acetate and water. The organic layer was dried over MgSO₄ and concentrated in vacuo. Purification by silica gel chromatography (Waters Prep-2000) using ethyl acetate/hexanes (25/75) gave 4.8 g (73%) of the title compound as a yellow solid. ¹ H NMR (CDCl₃) d 0.88 (t, J=7.45 Hz, 6H), 0.99-1.38 (m, 8H), 1.62-1.75 (m, 2H), 1.85-2.00 (m, 2H), 3.20 (s, 2H), 4.59 (s, 2H), 6.93 (dd, J=10.5 and 2.4 Hz, 1H), 7.15 (dt, J=8.4 and 2.85 Hz, 1H), 7.46-7.59 (m, 2H), 8.05-8.16 (m, 3H), 9.40 (S, 1H).

Step 3. Preparation of 3 ##STR436##

A solution of 4.8 g (10.4 mmol) of 2 in 500 mL THF was cooled to 0° C. in an ice bath. 20 mL of a 1 M solution of potassium t-butoxide was added slowly, maintaining the temperature at <5° C. Stirring was continued for 30 minutes, then the reaction was quenched with 100 mL of saturated ammonium chloride. The mixture was partitioned between ethyl acetate and water; the organic layer was washed with brine, then dried (MgSO₄) and concentrated in vacuo. Purification by silica gel chromatography through a 100 ml plug using CH₂ Cl₂ as eluent yielded 4.3 g (90%) of 3 as a pale yellow foam.

¹ H NMR (CDCl₃) d 0.93 (t, J=7.25 Hz, 6H), 1.00-1.55 (m, 8H), 1.59-1.74 (m, 3H), 2.15-2.95 (m, 1H), 3.16 (q_(AB), J_(AB) =15.0 Hz, ΔV=33.2 Hz, 2H), 4.17 (d, J=6.0 Hz, 1H), 5.67 (s, 1H), 6.34 (dd, J=9.6 and 3.0 Hz, 1H), 7.08 (dt, J=8.5 and 2.9 Hz, 1H), 7.64 (t, J=8.1 Hz, 1H), 7.81 (d, J=8.7 Hz, 1H), 8.13 (dd, J=9.9 and 3.6 Hz, 1H), 8.23-8.30 (m, 1H), 8.44 (s, 1H).

MS(FABH⁺) m/e (relative intensity) 464.5 (100), 446.6 (65). HRMS calculated for M+H 464.1907. Found 464.1905.

Step 4. Preparation of 4 ##STR437##

To a cooled (0° C.) solution of 4.3 g (9.3 mmol) of 3 in 30 ml THF contained in a stainless steel reaction vessel was added 8.2 g dimethyl amine (182 mmol). The vessel was sealed and heated to 110° C. for 16 hours. The reaction vessel was cooled to ambient temperature and the contents concentrated in vacuo. Purification by silica gel chromatography (Waters Prep-2000) using an ethyl acetate/hexanes gradient (10-40% ethyl acetate) gave 4.0 g (88%) of 4 as a yellow solid. ¹ H NMR (CDCl₃) d 0.80-0.95 (m, 6H), 0.96-1.53 (m, 8H), 1.60-1.69 (m, 3H), 2.11-2.28 (m, 1H), 2.79 (s, 6H), 3.09 (q_(AB), J_(AB) =15.0 Hz, DV=45.6 Hz, 2H), 4.90 (d, J=9.0 Hz, 1H), 5.65 (s, 1H), 5.75 (d, J=2.1 Hz, 1H), 6.52 (dd, J=9.6 and 2.7 Hz, 1H), 7.59 (t, J=8.4 Hz, 1H), 7.85 (d, J=7.80 Hz, 1H), 7.89 (d, J=9.0 Hz, 1H), 8.20 (dd, J=8.4 and 1.2 Hz, 1H), 8.43 (s, 1H).

MS(FABH⁺) m/e (relative intensity) 489.6 (100), 471.5 (25). HRMS calculated for M+H 489.2423. Found 489.2456.

Step 5. Preparation of 5 ##STR438##

To a suspension of 1.0 g (2.1 mmol) of 4 in 100 ml ethanol in a stainless steel Parr reactor was added 1 g 10% palladium on carbon. The reaction vessel was sealed, purged twice with H₂, then charged with H₂ (100 psi) and heated to 45° C. for six hours. The reaction vessel was cooled to ambient temperature and the contents filtered to remove the catalyst. The filtrate was concentrated in vacuo to give 0.9 g (96%) of 5. ¹ H NMR (CDCl₃) d 0.80-0.98 (m, 6H), 1.00-1.52 (m, 10H), 1.52-1.69 (m, 1H), 2.15-2.29 (m, 1H), 2.83 (s, 6H), 3.07 (q_(AB), J_(AB) =15.1 Hz, DV=44.2 Hz, 2H), 3.70 (s, 2H), 4.14 (s, 1H), 5.43 (s, 1H), 6.09 (d, J=2.4 Hz, 1H), 6.52 (dd, J=12.2 and 2.6 Hz, 1H), 6.65 (dd, J=7.8 and 1.8 Hz, 1H), 6.83 (s, 1H), 6.93 (d, J=7.50 Hz, 1H), 7.19 (t, J=7.6 Hz, 1H), 7.89 (d, J=8.9 Hz, 1H). MS(FABH⁺) m/e (relative intensity) 459.7 (100). HRMS calculated for M+H 459.2681. Found 459.2670.

Step 6. Preparation of 6

To a solution of 914 mg (2.0 mmol) of 5 in 50 ml THF was added 800 mg (4.0 mmol) 5-bromovaleroyl chloride. Next was added 4 g (39.6 mmol) TEA. The reaction was stirred 10 minutes, then partitioned between ethyl acetate and brine. The organic layer was dried (MgSO₄) and concentrated in vacuo. Purification by silica gel chromatography through a 70 ml MPLC column using a gradient of ethyl acetate(20-50%) in hexane as eluent yielded 0.9 g (73%) of 6 as a pale yellow oil. ¹ H NMR (CDCl₃) d 0.84-0.95 (m, 6H), 1.02-1.53 (m, 10H), 1.53-1.68 (m, 1H), 1.80-2.00 (m, 4H), 2.12-2.26 (m, 4H), 2.38 (t, J=6.9 Hz, 2H), 2.80 (s, 6H), 3.07 (q_(AB), J_(AB) =15.6 Hz, DV=40.4 Hz, 2H), 3.43 (t, J=6.9 Hz, 2H), 4.10 (s, 1H), 5.51 (s, 1H), 5.95 (d, J=2.4 Hz, 1H), 6.51 (dd, J=9.3 and 2.7 Hz, 1H), 7.28 (s, 1H), 7.32-7.41 (m, 2H), 7.78 (d, J=8.1 Hz, 1H), 7.90 (d, J=9.0 Hz, 1H).

Step 7. Preparation of 7 ##STR439##

To a solution of 0.9 g (1.45 mmol) of 6 in 25 ml acetonitrile add 18 g (178 mmol) TEA. Heat at 55° C. for 16 hours. The reaction mixture was cooled to ambient temperature and concentrated in vacuo. Purification by reverse-phase silica gel chromatography (Waters Delta Prep 3000) using an acetonitrile/water gradient containing 0.05% TFA (20-65% acetonitrile) gave 0.8 g (73%) of 7 as a white foam. ¹ H NMR (CDCl₃) d 0.80-0.96 (m, 6H), 0.99-1.54 (m, 19H), 1.59-1.84 (m, 3H), 2.09-2.24 (m, 1H), 2.45-2.58 (m, 2H), 2.81 (s, 6H), 3.09 (q_(AB), J_(AB) =15.6 Hz, DV=18.5 Hz, 2H), 3.13-3.31 (m, 8H), 4.16 (s, 1H), 5.44 (s, 1H), 6.08 (d, J=1.8 Hz, 1H), 6.57 (dd, J=9.3 and 2.7 Hz, 1H), 7.24 (t, J=7.5 Hz, 1H), 7.34 (t, J=8.4 Hz, 1H), 7.56 (d, J=8.4 Hz, 1H), 7.74 (s, 1H), 7.88 (d, J=9.0 Hz, 1H), 9.22 (s, 1H). HRMS calcd 642.4304; observed 642.4343.

Example 1398a

Step 1 ##STR440##

In an inert atmosphere, weigh out 68.3 gms phosphorus pentachloride (0.328 mole Aldrich 15,777-5) into a 2-necked 500 ml round bottom flask. Fit flask with a N₂ inlet adapter and suba seal. Remove from inert atmosphere and begin N₂ purge. Add 50 mls anhydrous chlorobenzene (Aldrich 28,451-3) to the PCl₅ via syringe and begin stirring with magnetic stir bar.

Weigh out 60 gms 2-chloro-5-nitrobenzoic acid (0.298 mole Aldrich 12,511-3). Slowly add to the chlorobenzene solution while under N₂ purge. Stir at room temperature overnight. After stirring at room temperature for ˜20 hrs, place in oil bath and heat at 50 C. for 1 hr. Remove chlorobenzene by high vacuum. Wash residue with anhydrous hexane. Dry acid chloride wt=61.95 gms. Store in inert and dry atmosphere.

In inert atmosphere, dissolve acid chloride with 105 mls anhydrous anisole (0.97 mole Aldrich 29,629-5) Place solution in a 2-necked 500 ml round bottom flask.

Weigh out 45.1 gms aluminum chloride (0.34 moles Aldrich 29,471-3) and place in a solid addition funnel. Fit reaction flask with addition funnel and a N₂ inlet adapter. Remove from inert atmosphere. Chill reaction solution with ice bath and begin N₂ purge. Slowly add AlCl₃ to chilled solution. After addition is complete, allow to warm to room temperature. Stir overnight.

Quench reaction by pouring into a solution of 300 mls 1N HCl and ice. Stir 15 min. Extract twice with ether. Combine organic layers and extract twice with 2% NaOH, then twice with deionized H₂ O. Dry with MgSO₄, filter and rotovap to dryness. Remove anisole by high vacuum. Crystalize product from 90% ethanol 10% ethyl acetate. Dry on vacuum line. Wt=35.2 gms. Yield 41%. Obtain NMR and mass spec (m/z=292).

Step 2 ##STR441##

Dissolve 38.10 gms (0.131 moles) of the benzophenone from step 1 in 250 mls anhydrous methylene chloride. Place in a 3 liter flask fitted with N₂ inlet, addition funnel and stopper. Stir with magnetic stir bar. Chill solution with ice bath.

Prepare a solution of 39.32 gms trifluoromethane sulfonic acid (0.262 mole Aldrich 15,853-4) and 170 mls anhydrous methylene chloride. Place in addition funnel and add dropwise to chilled solution under N₂. Stir 5 minutes after addition is complete.

Prepare a solution of 22.85 gms triethyl silane (0.197 mole Aldrich 23,019-7) and 170 mls anhydrous methylene chloride. Place in addition funnel and add dropwise to chilled solution under N₂. Stir 5 minutes after addition is complete.

Prepare a second solution of 39.32 gms trifluoromethane sulfonic acid and 170 mls anhydrous methylene chloride. Place in addition funnel and add dropwise to chilled solution under N₂. Stir 5 minutes after addition is complete.

Prepare a second solution of 22.85 gms triethyl silane and 170 mls anhydrous methylene chloride. Place in addition funnel and add dropwise to chilled solution under N₂. After all additions are made allow to slowly warm to room temperature overnight. Stir under N₂ overnight.

Prepare 1300 mls saturated NaHCO₃ in a 4 liter beaker. Chill with ice bath. While stirring vigorously, slowly add reaction mixture. Stir at chilled temperature for 30 min. Pour into a separatory funnel and allow separation. Remove organic layer and extract aqueous layer 2 times with methylene chloride. Dry organic layers with MgSO₄. Crystallize from ethanol. Dry on vacuum line. Dry wt=28.8 gms. Confirm by NMR and mass spec (m/z=278).

Step 3 ##STR442##

Dissolve 10.12 gms (0.036 moles) of product 2 with 200 mls anhydrous DMSO. Place in a 500 ml round bottom flask with magnetic stir bar. Fit flask with water condenser, N₂ inlet, and stopper. Add 1.84 gms Li₂ S (0.040 moles Aldrich 21,324-1). Place flask in oil bath and heat at 75° C. under N₂ overnight then cool to room temperature.

Weigh out 10.59 gms dibutyl mesylate (0.040 moles). Dissolve with anhydrous DMSO and add to reaction solution. Purge well with N₂, heat overnight at 80° C.

Cool to room temperature. Prepare 500 mls of 5% acetic acid in a 2 liter beaker. While stirring, slowly add reaction mixture. Stir 30 min. Extract with ether 3 times. Combine organic layers and extract with water and sat'd NaCl. Dry organic layer with MgSO₄, filter and rotovap to dryness. Dry oil on vacuum line. Obtain pure product by column chromatography using 95% hexane and 5% ethyl acetate as the mobile phase. Dry wt=7.8 gms. Obtain NMR and mass spec (m/z=444).

Step 4 ##STR443##

Dissolve 9.33 gms (0.021 moles) of product 3 with 120 mls anhydrous methylene chloride. Place in a 250 ml round bottom flask with magnetic stir bar. Fit flask with N₂ inlet and stopper. Chill solution with ice bath under N₂ purge. Slowly add 11.54 gms 3-chloroperbenzoic acid (0.0435 moles, Fluka 25800, ˜65%). After addition is complete warm to room temperature and monitor reaction by TLC. Reaction goes quickly to the sulphoxide intermediate but takes 8 hrs to convert to the sulphone. Chill solution over night in freezer. Filter solid from reaction, extract filtrate with 10% K₂ Co₃. Extract aqueous layer twice with methylene choride. Combine organic layers and dry with MgSO₄. Filter and rotovap to dryness. Obtain pure product by crystallizing from ethanol or isolating by column chromatography. Obtain NMR and mass spec (m/z=476).

Step 5 ##STR444##

Reaction is done in a 300 ml stainless steel Parr stirred mini reactor. Place 9.68 gms (0.0204 moles) of product 4 in reactor base. Add 160 mls ethanol. For safety reasons next two compounds are added in a N₂ atmosphere glove bag. In glove bag, add 15.3 mls formaldehyde (0.204 moles, Aldrich 25,254-9, about 37 wt % in water) and 1.45 gms 10% Pd/Carbon (Aldrich 20,569-9). Seal reactor before removing from glove bag. Purge reactor three times with H₂. Heat to 55° C. under H₂. Run reaction at 200 psig H₂, 55° C., and a stir rate of 250 rpm. Run overnight under these conditions.

Cool reactor and vent H₂. Purge with N₂. Check progress of run by TLC. Reaction is a mixture of desired product and intermediate. Filter reaction mixture over a bed of celite washing well with ether. Rotovap and redissolve with ether. Extract with water. Dry organic layer with MgSO₄, filter and rotovap to dryness. Dry on vacuum line.

Charge reactor again with same amounts, seal reactor and run overnight under same conditions. After second run all of the material has been converted to the desired product. Cool and vent H₂ pressure. Purge with N₂. Filter over a bed of celite, washing well with ether. Rotovap to dryness. Dissolve with ether and extract with water. Dry organic layer with MgSO₄, filter and rotovap to dryness. Dry on vacuum line. Obtain NMR and mass spec (m/z=474).

Step 6 ##STR445##

Dissolve 8.97 gms (0.0189 mole) of product 5 with 135 mls anhydrous THF. Place in a 250 ml round bottom flask with magnetic stir bar. Fit flask with N₂ inlet and stopper. Chill solution with ice/salt bath under N₂ purge. Slowly add 2.55 gms potassium t-butoxide (0.227 mole Aldrich 15,667-1). After addition is complete, continue to stir at -10° C. monitoring by TLC. Once reaction is complete, quench by adding 135 mls 10% HCl stirring 10 min. Extract three times with ether. Dry organic layer with MgSO₄, filter and rotovap to dryness. Crystallize from ether. Obtain NMR and mass spec (m/z=474).

Step 7 ##STR446##

Dissolve 4.67 gms (0.01 moles) of product 6 with 100 mls anhydrous chloroform. Place in a 250 ml round bottom flask with magnetic stir bar. Fit flask with N₂ inlet adapter and suba seal. Chill solution with dry ice/acetone bath under a N₂ purge. Slowly add, via syringe, 2.84 mls boron tribromide (0.03 moles Aldrich 20,220-7). Stir at cold temperature for 15 min after addition then allow to warm to room temperature. Monitor reaction progress by TLC. Reaction is usually complete in 3 hrs.

Chill solution with ice bath. Quench with 100 mls 10% K₂ CO₃ while stirring rapidly. Stir 10 min. then transfer to sep funnel and allow separation. Remove aqueous layer. Extract organic layer once with 10% HCl, once H₂ O, and once with saturated NaCl solution. Dry organic layer with MgSO₄, filter and rotovap to dryness. Crystallize product from ether. Obtain NMR and mass spec (m/z=460).

Step 8 ##STR447##

Weigh 0.38 gms NaH (9.57 mmoles Aldrich 19,923-0 60% disp. in mineral oil) in a 250 ml round bottom flask with magnetic stir bar. Fit flask with N₂ inlet and stopper. Chill NaH with ice bath and begin N₂ purge.

Dissolve 4.0 gms (8.7 mmoles) of product 7 with 60 mls anhydrous DMF. Add to the cold NaH. Stir at cold temperature for 30 min. Add 1.33 gms K₂ CO₃ (9.57 mmoles Fisher P-208).

Dissolve 16.1 gms 1,2-bis-(2-iodoethoxy)ethane (43.5 mmoles Aldrich 33,343-3) with 60 mls anhydrous DMF. Add to cold reaction mixture. Warm to room temperature then heat to 40° C. overnight under N₂.

Cleanup by diluting with ether and extracting sequentially with 5% NaOH, H₂ O, and saturated NaCl. Dry organic layer with MgSO₄, filter and dry. Obtain pure product by column chromatography using 75% hexane 25% ethyl acetate as the mobile phase. Obtain NMR and mass spec (m/z=702).

Step 9 ##STR448##

Dissolve 1.0 gms (1.43 mmoles) of product 8 with 10 mls anhydrous acetonitrile. Place in a 3 ounce Fischer-Porter pressure reaction vessel with magnetic stir bar. Add 2.9 gms triethyl amine (28.6 mmoles Aldrich 23,962-3) dissolved in 10 mls anhydrous acetonitrile. Purge well with N₂ then close system Heat at 45° C. Monitor reaction by TLC. Reaction is usually complete in 48 hrs.

Perform cleanup by removing acetonitrile under vacuum. Redissolve with anhydrous chloroform and precipitate quaternary ammonium salt with ether. Repeat several times. Dry to obtain crystalline product. Obtain NMR and mass spec (m/z=675).

Example 1399

Step 1. Preparation of 1 ##STR449##

To a solution of 144 g of KOH (2560 mmol) in 1.1 L of DMSO was added 120 g of 2-bromobenzyl alcohol (641 mmol) slowly via addition funnel. Then was added 182 g of methyliodide (80 mL, 1282 mmol) via addition funnel. Stirred at ambient temperature for fifteen minutes. Poured reaction contents into 1.0 L of water and extracted three times with ethyl acetate. The organic layer was dried over MgSO₄ and concentrated in vacuo. Purified by silica-gel chromatography through a 200 mL plug using hexanes (100%) as elutant yielded 103.2 g (80%) of 1 as a clear colorless liquid. ¹ H NMR (CDCl₃) d 3.39 (s, 3H), 4.42 (s, 2H), 7.18-7.27 (m, 2H), 7.12 (d, J=7.45, 1H), 7.50 (s, 1H).

Step 2. Preparation of 2 ##STR450##

To a cooled (-78° C.) solution of 95 g (472 mmol) of 1 in 1.5 L THF was added 240 mL of 2.5 M n-butyl lithium (576 mmol). The mixture was stirred for one hour, and then to it was added 180 g of zinc iodide (566 mmol) dissolved in 500 ml THF. The mixture was stirred thirty minutes, allowed to warm to 5 C., cooled to -10° C. and to it was added 6 g of Pd(PPh₃)₄ (5.2 mmol) and 125 g 2,5-difluorobenzoyl chloride (708 mmol). The mixture was stirred at ambient temperature for 18 hours and then cooled to 10° C., quenched with water, partitioned between ethyl acetate and water, and washed organic layer with 1N HCL and with 1N NaOH. The organic layer was dried over MgSO₄ and concentrated in vacuo. Purification by silica gel chromatography (Waters Prep-500) using 5% ethyl acetate/hexanes as elutant gave 53.6 g (43%) of 2 as an orange oil. ¹ H NMR (CDCl₃) d 3.40 (s, 3H), 4.51 (s, 2H), 7.12-7.26 (m, 3H), 7.47 (t, J=7.50, 1H), 7.57 (d, J=7.45, 1H), 7.73 (d, J=7.45, 1H), 7.80 (s, 1H).

Step 3. Preparation of 3 ##STR451##

A solution of 53 g (202.3 mmol) of 2 and 11.2 g Li2S (242.8 mmol) in 250 mL DMF was heated to 100° C. for 18 hours. The reaction was cooled (0° C.) and 60.7 g of X' (the cyclic sulfate compound of example 1397) (242.8 mmol) in 50 mL DMF was added. Stirred at ambient temperature for 18 hours then condensed in vacuo. Added 1 L water to organic residue and extracted twice with diethyl ether. Aqueous layer acidified (pH 1) and refluxed 2 days. Cooled to ambient temperature and extracted with methylene chloride, dried organic layer over MgSO₄ and condensed in vacuo. Purification by silica gel chromatography (Waters Prep-500) using 10% ethyl acetate/hexanes as elutant gave 42.9 g (48%) of 3 as a yellow oil. ¹ H NMR (CDCl₃) d 0.86 (t, J=7.25 Hz, 6H), 1.10-1.26 (m, 12H), 2.83 (s, 2H), 3.32 (s, 2H), 3.40 (s, 3H), 4.48 (s, 3H), 7.02 (dd, J=8.26 Hz and 2.82 Hz, 1H), 7.16 (dt, J=8.19 Hz and 2.82 Hz, 1H), 7.45 (t, J=7.65 Hz, 1H), 7.56-7.61 (m, 2H), 7.69 (d, J=7.85 Hz, 1H), 7.74 (s, 1H).

Step 4. Preparation of 4 ##STR452##

To a cooled (-40° C.) solution of 42.9 g (96.2 mmol) of 3 in 200 mL of methylene chloride was added 21.6 g trifluoromethane sulfonic acid (12.8 mL, 144 mmol) followed by the addition of 22.4 g triethyl silane (30.7 mL, 192.4 mmol). Stirred at -20° C. for two hours, quenched with water and warmed to ambient temperature. Partitioned between methylene chloride and water, dried the organic layer over MgSO₄ and condensed in vacuo. Purification by silica gel chromatography (Waters Prep-500) using 10% ethyl acetate/hexanes as elutant gave 24.2 g (60%) of 4 as a oil. ¹ H NMR (CDCl₃) d 0.89 (t, J=7.05 Hz, 6H), 1.17-1.40 (m, 12H), 1.46 (t, J=5.84 Hz, 1H), 2.81 (s, 2H), 3.38 (s, 3H), 3.43 (d, J=5.23 Hz, 2H), 4.16 (s, 2H), 4.42 (s, 2H), 6.80 (d, J=9.67 Hz, 1H), 6.90 (t, J=8.46 Hz, 1H), 7.09 (d, J=7.45 Hz, 1H), 7.15-7.21 (m, 2H), 7.25-7.32 (m, 2H), 7.42 (m, 1H).

Step 5. Preparation of 5 ##STR453##

To a cooled (15-18° C.) solution of 24.2 g (55.8 mmol) of 4 in 100 mL DMSO was added 31.2 g sulfur trioxide pyridine complex (195 mmol). Stirred at ambient temperature for thirty minutes. Poured into cold water and extracted three times with ethyl acetate. Washed organics with 5% HCl (300 mL) and then with brine (300 mL), dired organics over MgSO₄ and condensed in vacuo to give 23.1 g (96%) of 5 as a light brown oil. ¹ H NMR (CDCl₃) d 0.87 (t, J=7.05 Hz, 6H), 1.01-1.32 (m, 8H), 1.53-1.65 (m, 4H), 2.98 (s, 2H), 3.38 (s, 3H), 4.15 (s, 2H), 4.43 (s, 2H), 6.81 (dd, J=9.66 Hz and 2.82 Hz, 1H), 6.91 (t, J=8.62 Hz, 1H), 7.07 (d, J=7.46 Hz, 1H), 7.14 (s, 1H), 7.19 (d, J=7.65 Hz, 1H), 7.26-7.32 (m, 1H), 7.42 (dd, J=8.66 Hz and 5.64 Hz, 1H), 9.40 (s, 1H).

Step 6. Preparation of 6 ##STR454##

To a cooled (0° C.) solution of 23.1 g (53.6 mmol) of 5 in 200 mL methylene chloride was added 28.6 g meta cholorperoxy-benzoic acid (112.6 mmol). Stirred at ambient temperature for 24 hours. Quenched with 100 mL 10% Na₂ SO₃, partitioned between water and methylene chloride. Dried organic layer over MgSO₄ and condensed in vacuo to give 24.5 g (98%) of 6 as a light yellow oil. ¹ H NMR (CDCl₃) d 0.86-1.29 (m, 14H), 1.58-1.63 (m, 2H), 1.82-1.91 (m, 2H), 3.13 (s, 2H), 3.39 (s, 3H), 4.44 (s, 2H), 4.50 (s, 2H), 6.93 (d, J=9.07 Hz, 1H), 7.10-7.33 (m, 5H), 8.05 (s, 1H), 9.38 (s, 1H).

Step 7. Preparation of 7 ##STR455##

To a solution of 24.5 g (52.9 mmol) of 6 in 20 mL of THF contained in a stainless steel reaction vessel was added 100 mL of a 2.0 M solution of dimethyl amine and 20 mL of neat dimethyl amine. The vessel was sealed and heated to 110° C. for 16 hours. The reaction vessel was cooled to ambient temperature and the contents concentrated in vacuo. Purification by silica gel chromatography (Waters Prep-500) using 15% ethyl acetate/hexanes gave 21.8 g (84%) of 7 as a clear colorless oil. ¹ H NMR (CDCl₃) d 0.85 (t, J=7.25 Hz, 6H), 0.93-1.29 (m, 8H), 1.49-1.59 (m, 2H), 1.70-1.80 (m, 2H), 2.98 (s, 8H), 3.37 (s, 3H), 4.41 (s, 2H), 4.44 (s, 2H), 6.42 (s, 1H), 6.58 (dd, J=9.0 Hz and 2.61 Hz, 1H), 7.13 (d, J=7.45 Hz, 1H), 7.21 (s, 1H), 7.28 (t, J=7.85 Hz, 1H), 7.82 (d, J=9.06 Hz, 1H), 9.36 (s, 1H).

Step 8. Preparation of 8 ##STR456##

A solution of 21.8 g (44.8 mmol) of 7 in 600 mL of THF was cooled to 0° C. 58.2 mL of a 1 M solution of potassium t-butoxide was added slowly, maintaining the temperature at <5° C. Stirred for 30 minutes, then quenched with 50 mL of saturated ammonium chloride. The organic layer was partitioned between ethyl acetate and water, dried over MgSO₄ and concentrated in vacuo. Purification by recrystalization from ˜10% ethyl acetate/hexanes gave 15.1 g of 8 as a white solid. The mother liquor was purified by silica gel chromatography (Waters Prep-500) using 30% ethyl acetate/hexanes as the elutant to give 3.0 g of 8 as a white solid. MS (FABLi⁺) m/e 494.6. HRMS (EI⁺) calculated for M+H 487.2756. Found 487.2746.

Step 9. Preparation of 9 ##STR457##

A solution of 2.0 g (4.1 mmol) of 8 in 20 mL of methylene chloride was cooled to -60° C. 4.1 mL of a 1M solution of boron tribromide was added. Stirred at ambient temperature for thirty minutes. Cooled reaction to -10° C. and quenched with 50 mL of water. The organic layer was partitioned between methylene chloride and water, dried over MgSO₄ and concentrated in vacuo. Purification by recrystalization from 50% ethyl acetate/methylene chloride gave 1.95 g (89%) of 9 as a white solid. MS (FABH⁺) m/e 537. HRMS (FAB) calculated for M 536.1834. Found 536.1822.

Step 10. Preparation of 10 ##STR458##

A solution of 1.09 g (2.0 mmol) of 9 and 4.9 g (62 mmol) of pyridine in 30 mL of acetonitrile was stirred at ambient temperature for 18 hours. The reaction was concentrated in vacuo. Purification by recrystallization from methanol/diethyl ether gave 1.19 g (96%) of 10 as an off white solid. MS (FAB⁺) m/e 535.5.

Example 1400

Step 1 ##STR459##

A 12-liter, 4-neck round-bottom flask was equipped with reflux condenser, N₂ gas adaptor, mechanical stirrer, and an addition funnel. The system was purged with N₂. A slurry of sodium hydride (126.0 g/4.988 mol) in toluene (2.5 L) was added, and the mixture was cooled to 6° C. A solution of 4-fluorophenol (560.5 g/5.000 mol) in toluene (2.5 L) was added via addition funnel over a period of 2.5 h. The reaction mixture was heated to reflux (100 C.) for 1 h. A solution of 3-methoxybenzyl chloride (783.0 g/5.000 mol) in toluene (750 mL) was added via addition funnel while maintaining reflux. After 15 h. refluxing, the mixture was cooled to room temperature and poured into H₂ O (2.5 L). After 20 min. stirring, the layers were separated, and the organic layer was extracted with a solution of potassium hydroxide (720 g) in MeOH (2.5 L). The MeOH layer was added to 20% aqueous potassium hydroxide, and the mixture was stirred for 30 min. The mixture was then washed 5 times with toluene. The toluene washes were extracted with 20% aq. KOH. All 20% aq. KOH solutions were combined and acidified with concentrated HCl. The acidic solution was extracted three times with ethyl ether, dried (MgSO₄), filtered and concentrated in vacuo. The crude product was purified by Kugelrohr distillation to give a clear, colorless oil (449.0 g/39% yield). b.p.: 120-130 C./50 mtorrHg. ¹ H NMR and MS [(M+H)⁺ =233] confirmed desired structure.

Step 2 ##STR460##

A 12-liter, 3-neck round-bottom flask was fitted with mechanical stirrer and N₂ gas adaptor. The system was purged with N₂. 4-Fluoro-2-(3-methoxybenzyl)-phenol (455.5 g/1.961 mol) and dimethylformamide were added. The solution was cooled to 6 C., and sodium hydride (55.5 g/2.197 mol) was added slowly. After warming to room temperature, dimethylthiocarbamoyl chloride (242.4 g/1.961 mol) was added. After 15 h, the reaction mixture was poured into H₂ O (4.0 L), and extracted two times with ethyl ether. The combined organic layers were washed with H₂ O and saturated aqueous NaCl, dried (MgSO₄), filtered, and concentrated in vacuo to give the product (605.3 g, 97% yield). ¹ H NMR and MS [(M+H)⁺ 320] confirm desired structure.

Step 3 ##STR461##

A 12-liter, round-bottom flask was equipped with N₂ gas adaptor, mechanical stirrer, and reflux condenser. The system was purged with N₂. 4-Fluoro-2-(3-methoxybenzyl)-phenyldimethylthiocarbamate (605.3 g/1.895 mol) and phenyl ether (2.0 kg) were added, and the solution was heated to reflux for 2 h. The mixture was stirred for 64 h. at room temperature and then heated to reflux for 2 h. After cooling to room temperature, MeOH (2.0 L) and THF (2.0 L) were added, and the solution was stirred for 15 h. Potassium hydroxide (425.9 g/7.590 mol) was added, and the mixture was heated to reflux for 4 h. After cooling to room temperature, the mixture was concentrated by rotavap, dissolved in ethyl ether (1.0 L), and extracted with H₂ O. The aqueous extracts were combined, acidified with concentrated HCl, and extracted with ethyl ether. The ether extracts were dried (MgSO₄), filtered, and concentrated in vacuo to give an amber oil (463.0 g, 98% yield). ¹ H NMR confirmed desired structure.

Step 4 ##STR462##

A 5-liter, 3-neck, round-bottom flask was equipped with N₂ gas adaptor and mechanical stirrer. The system was purged with N₂. 4-Fluoro-2-(3-methoxybenzyl)-thiophenol (100.0 g/403.2 mmol) and 2-methoxyethyl ether (1.0 L) were added and the solution was cooled to 0° C. Sodium hydride (9.68 g/383.2 mmol) was added slowly, and the mixture was allowed to warm to room temperature, 2,2-Dibutylpropylene sulfate (110.89 g/443.6 mmol) was added, and the mixture was stirred for 64 h. The reaction mixture was concentrated by rotavap and dissolved in H₂ O. The aqueous solution was washed with ethyl ether, and concentrated H₂ SO₄ was added. The aqueous solution was heated to reflux for 30 min, cooled to room temperature, and extracted with ethyl ether. The ether solution was dried (MgSO₄), filtered, and conc'd in vacuo to give an amber oil (143.94 g/85% yield). ¹ H NMR and MS [(M+H)⁺ =419] confirm the desired structure.

Step 5 ##STR463##

A 2-liter, 4-neck, round-bottom flask was equipped with N₂ gas adaptor, and mechanical stirrer. The system was purged with N₂. The corresponding alcohol (143.94 g/343.8 mmol) and CH₂ Cl₂ (1.0 L) were added and cooled to 0 C. Pyridinium chlorochromate (140.53 g/651.6 mmol) was added. After 6 h., CH₂ Cl₂ was added. After 20 min, the mixture was filtered through silica gel, washing with CH₂ Cl₂. The filtrate was concentrated in vacuo to give a dark yellow-red oil (110.6 g, 77% yield). ¹ H NMR and MS [(M+H)⁺ =417] confirm the desired structure.

Step 6 ##STR464##

A 2-liter, 4-neck, round-bottom flask was equipped with N₂ gas adaptor and mechanical stirrer. The system was purged with N₂. The corresponding sulfide (110.6 g/265.5 mmol) and CH₂ Cl₂ (1.0 L) were added. The solution was cooled to 0 C., and 3-chloroperbenzoic acid (158.21 g/531.7 mmol) was added portionwise. After 30 min, the reaction mixture was allowed to warm to room temperature After 3.5 h, the reaction mixture was cooled to 0 C. and filtered through a fine fritted funnel. The filtrate was washed with 10% aqueous K₂ CO₃. An emulsion formed which was extracted with ethyl ether. The organic layers were combined, dried (MgSO₄), filtered, and concentrated in vacuo to give the product (93.2 g, 78% yield). ¹ H NMR confirmed the desired structure.

Step 7 ##STR465##

A 2-liter, 4-neck, round-bottom flask was equipped with N₂ gas adaptor, mechanical stirrer, and a powder addition funnel. The system was purged with N₂. The corresponding aldehyde (93.2 g/208 mmol) and THF (1.0 L) were added, and the mixture was cooled to 0 C. Potassium tert-butoxide (23.35 g/208.1 mmol) was added via addition funnel. After 1 h, 10% aq/HCl (1.0 L) was added. After 1 h, the mixture was extracted three times with ethyl ether, dried (MgSO₄), filtered, and concentrated in vacuo. The crude product was purified by recryst. from 80/20 hexane/ethyl acetate to give a white solid (32.18 g). The mother liquor was concentrated in vacuo and recrystelized from 95/5 toluene/ethyl acetate to give a white solid (33.60 g/combined yield: 71%). ¹ H NMR confirmed the desired product.

Step 8 ##STR466##

A Fisher porter bottle was fitted with N₂ line and magnetic stirrer. The system was purged with N₂. The corresponding fluoro-compound (28.1 g/62.6 mmol) was added, and the vessel was sealed and cooled to -78° C. Dimethylamine (17.1 g/379 mmol) was condensed via a CO₂ /acetone bath and added to the reaction vessel. The mixture was allowed to warm to room temperature and was heated to 60° C. After 20 h, the reaction mixture was allowed to cool and was dissolved in ethyl ether. The ether solution was washed with H₂ O, saturated aqueous NaCl, dried (MgSO₄), filtered, and concentrated in vacuo to give a white solid (28.5 g/96% yield). ¹ H NMR confirmed the desired structure.

Step 9 ##STR467##

A 250-mL, 3-neck, round-bottom flask was equipped with N₂ gas adaptor and magnetic stirrer. The system was purged with N₂. The corresponding methoxy-compound (6.62 g/14.0 mmol) and CHCl₃ (150 mL) were added. The reaction mixture was cooled to -78 C., and boron tribromide (10.50 g/41.9 mmol) was added. The mixture was allowed to warm to room temperature After 4 h, the reaction mixture was cooled to 0 C. and was quenched with 10% K₂ CO₃ (100 mL). After 10 min, the layers were separated, and the aqueous layer was extracted two times with ethyl ether. The CHCl₃ and ether extracts were combined, washed with saturated aqueous NaCl, dried (MgSO₄), filtered, and concentrated in vacuo to give the product (6.27 g/98% yield). ¹ H NMR confirmed the desired structure.

Step 10 ##STR468##

In a 250 ml single neck round bottom Flask with stir bar place 2-diethylamineoethyl chloride hydochloride (fw 172.10 g/mole) Aldrich D8, 720-1 (2.4 mmol, 4.12 g), 34 ml dry ether and 34 ml of 1N KOH(aqueous). Stir 15 minutes and then separate by ether extraction and dry over anhydrous potassium carbonate.

In a separate 2-necked 250 ml round bottom flask with stir bar add sodium hydride (60% dispersion in mineral oil, 100 mg , 2.6 mmol) and 34 ml of DMF. Cool to ice temperature. Next add phenol product(previous step) 1.1 g (2.4 mmilomoles in 5 ml DMF and the ether solution prepared above. Heat to 40 C. for 3 days. The product which contained no starting material by TLC was diluted with ether and extracted with 1 portion of 5% NaOH, followed by water and then brine. The ether layer was dried over magnesium sulfate and isolated by removing ether by rotary evaporation (1.3 gms).The product may be further purified by chromatography (SiO2 99% ethyl acetate/1% NH4OH at 5 ml/min.). Isolated yield: 0.78 g (mass spec, and H1 NMR)

Step 11 ##STR469##

The product from step 10 (0.57 gms, 1.02 millimole fw 558.83 g/mole) and 1.6 gms iodoethane (10.02 mmol) was placed in 5 ml acetonitrile in a fischer-porter bottle and heated to 45 C. for 3 days. The solution was evaporated to dryness and redissolved in 5 mls of chloroform. Next ether was added to the chloroform solution and the resulting mixture was chilled. The desired product is isolated as a precipitate 0.7272 gms. Mass spec M-I=587.9, H NMR).

Example 1401

Step 1 ##STR470##

A 12-liter, 4-neck round-bottom flask was equipped with reflux condenser, N₂ gas adaptor, mechanical stirrer, and an addition funnel. The system was purged with N₂. A slurry of sodium hydride (126.0 g/4.988 mol) in toluene (2.5 L) was added, and the mixture was cooled to 6 C. A solution of 4-fluorophenol (560.5 g/5.000 mol) in toluene (2.5 L) was added via addition funnel over a period of 2.5 h. The reaction mixture was heated to reflux (100 C.) for 1 h. A solution of 3-methoxybenzyl chloride (783.0 g/5.000 mol) in toluene (750 mL) was added via addition funnel while maintaining reflux. After 15 h. refluxing, the mixture was cooled to room temperature and poured into H₂ O (2.5 L). After 20 min. stirring, the layers were separated, and the organic layer was extracted with a solution of potassium hydroxide (720 g) in MeOH (2.5 L). The MeOH layer was added to 20% aqueous potassium hydroxide, and the mixture was stirred for 30 min. The mixture was then washed 5 times with toluene. The toluene washes were extracted with 20% aq. KOH. All 20% aqueous KOH solutions were combined and acidified with concentrated HCl. The acidic solution was extracted three times with ethyl ether, dried over MgSO₄, filtered and concentrated in vacuo. The crude product was purified by Kugelrohr distillation to give a clear, colorless oil (449.0 g/39% yield). b.p.: 120-130 C./50 mtorrHg. ¹ H NMR and MS [(M+H)⁺ =233] confirmed desired structure.

Step 2 ##STR471##

A 12-liter, 3-neck round-bottom flask was fitted with mechanical stirrer and N₂ gas adaptor. The system was purged with N₂. 4-Fluoro-2-(3-methoxybenzyl)-phenol (455.5 g/1.961 mol) and dimethylformamide were added. The solution was cooled to 6 C., and sodium hydride (55.5 g/2.197 mol) was added slowly. After warming to room temperature, dimethylthiocarbamoyl chloride (242.4 g/1.961 mol) was added. After 15 h, the reaction mixture was poured into H₂ O (4.0 L), and extracted two times with ethyl ether. The combined organic layers were washed with H₂ O and saturated aqueous NaCl, dried over MgSO₄, filtered, and concentrated in vacuo to give the product (605.3 g, 97% yield). ¹ H NMR and MS [(M+H)⁺ =320] confirm desired structure.

Step 3 ##STR472##

A 12-liter, round-bottom flask was equipped with N₂ gas adaptor, mechanical stirrer, and reflux condenser. The system was purged with N₂. 4-Fluoro-2-(3-methoxybenzyl)-phenyldimethylthiocarbamate (605.3 g/1.895 mol) and phenyl ether (2.0 kg) were added, and the solution was heated to reflux for 2 h. The mixture was stirred for 64 h. at room temperature and then heated to reflux for 2 h. After cooling to room temperature, MeOH (2.0 L) and THF (2.0 L) were added, and the solution was stirred for 15 h. Potassium hydroxide (425.9 g/7.590 mol) was added, and the mixture was heated to reflux for 4 h. After cooling to room temperature, the mixture was concentrated by rotavap, dissolved in ethyl ether (1.0 L), and extracted with H₂ O. The aqueous extracts were combined, acidified with conc. HCl, and extracted with ethyl ether. The ether extracts were dried (MgSO₄), filtered, and concentrated in vacuo to give an amber oil (463.0 g, 98% yield). ¹ H NMR confirmed desired structure.

Step 4 ##STR473##

A 5-liter, 3-neck, round-bottom flask was equipped with N₂ gas adaptor and mechanical stirrer. The system was purged with N₂. 4-Fluoro-2-(3-methoxybenzyl)-thiophenol (100.0 g/403.2 mmol) and 2-methoxyethyl ether (1.0 L) were added and the solution was cooled to 0 C. Sodium hydride (9.68 g/383.2 mmol) was added slowly, and the mixture was allowed to warm to room temperature 2,2-Dibutylpropylene sulfate (110.89 g/443.6 mmol) was added, and the mixture was stirred for 64 h. The reaction mixture was concentrated by rotavap and dissolved in H₂ O. The aqueous solution was washed with ethyl ether, and conc. H₂ SO₄ was added. The aqueous solution was heated to reflux for 30 min, cooled to room temperature, and extracted with ethyl ether. The ether solution was dried (MgSO₄), filtered, and concentrated in vacuo to give an amber oil (143.94 g/85% yield). ¹ H NMR and MS [(M+H)⁺ =419] confirm the desired structure.

Step 5 ##STR474##

A 2-liter, 4-neck, round-bottom flask was equipped with N₂ gas adaptor, and mechanical stirrer. The system was purged with N₂. The corresponding alcohol (143.94 g/343.8 mmol) and CH₂ Cl₂ (1.0 L) were added and cooled to 0 C. Pyridinium chlorochromate (140.53 g/651.6 mmol) was added. After 6 h., CH₂ Cl₂ was added. After 20 min, the mixture was filtered through silica gel, washing with CH₂ Cl₂. The filtrate was concentrated in vacuo to give a dark yellow-red oil (110.6 g, 77% yield). ¹ H NMR and MS [(M+H)⁺ =417] confirm the desired structure.

Step 6 ##STR475##

A 2-liter, 4-neck, round-bottom flask was equipped with N₂ gas adaptor and mechanical stirrer. The system was purged with N₂. The corresponding sulfide (110.6 g/265.5 mmol) and CH₂ Cl₂ (1.0 L) were added. The solution was cooled to 0 C., and 3-chloroperbenzoic acid (158.21 g/531.7 mmol) was added portionwise. After 30 min, the reaction mixture was allowed to warm to room temperature After 3.5 h, the reaction mixture was cooled to 0 C. and filtered through a fine fritted funnel. The filtrate was washed with 10% aqueous K₂ CO₃. An emulsion formed which was extracted with ethyl ether. The organic layers were combined, dried (MgSO₄), filtered, and concentrated in vacuo to give the product (93.2 g, 78% yield). ¹ H NMR confirmed the desired structure.

Step 7 ##STR476##

A 2-liter, 4-neck, round-bottom flask was equipped with N₂ gas adaptor, mechanical stirrer, and a powder addition funnel. The system was purged with N₂. The corresponding aldehyde (93.2 g/208 mmol) and THF (1.0 L) were added, and the mixture was cooled to 0 C. Potassium tert-butoxide (23.35 g/208.1 mmol) was added via addition funnel. After 1 h, 10% aq/HCl (1.0 L) was added. After 1 h, the mixture was extracted three times with ethyl ether, dried (MgSO₄), filtered, and concentrated in vacuo. The crude product was purified by recrystallized from 80/20 hexane/ethyl acetate to give a white solid (32.18 g). The mother liquor was concentrated in vacuo and recrystallized from 95/5 toluene/ethyl acetate to give a white solid (33.60 g, combined yield: 71%). ¹ H NMR confirmed the desired product.

Step 8 ##STR477##

A Fisher porter bottle was fitted with N₂ line and magnetic stirrer. The system was purged with N₂. The corresponding fluoro-compound (28.1 g/62.6 mmol) was added, and the vessel was sealed and cooled to -78° C. Dimethylamine (17.1 g/379 mmol) was condensed via a CO₂ /acetone bath and added to the reaction vessel. The mixture was allowed to warm to room temperature and was heated to 60 C. After 20 h, the reaction mixture was allowed to cool and was dissolved in ethyl ether. The ether solution was washed with H₂ O, saturated aqueous NaCl, dried over MgSO₄, filtered, and concentrated in vacuo to give a white solid (28.5 g/96% yield). ¹ H NMR confirmed the desired structure.

Step 9 ##STR478##

A 250-mL, 3-neck, round-bottom flask was equipped with N₂ gas adaptor and magnetic stirrer. The system was purged with N₂. The corresponding methoxy-compound (6.62 g/14.0 mmol) and CHCl₃ (150 mL) were added. The reaction mixture was cooled to -78 C., and boron tribromide (10.50 g/41.9 mmol) was added. The mixture was allowed to warm to room temperature After 4 h, the reaction mixture was cooled to 0 C. and was quenched with 10% K₂ CO₃ (100 mL). After 10 min, the layers were separated, and the aqueous layer was extracted two times with ethyl ether. The CHCl₃ and ether extracts were combined, washed with saturated aqueous NaCl, dried over MgSO₄, filtered, and concentrated in vacuo to give the product (6.27 g/98% yield). ¹ H NMR confirmed the desired structure.

Step 10 ##STR479##

In a 250 ml single neck round bottom flask with stir bar place 2-diethylamineoethyl chloride hydochloride (fw 172.10 g/mole) Aldrich D8, 720-1 (2.4 millimoles, 4.12 g), 34 ml dry ether and 34 ml of 1N KOH (aqueous). Stir 15 minutes and then separate by ether extraction and dry over anhydrous potassium carbonate.

In a separate 2-necked 250 ml round bottom flask with stir bar add sodium hydride (60% dispersion in mineral oil, 100 mg, (2.6 mmol) and 34 ml of DMF. Cool to ice temperature. Next add phenol product (previous step) 1.1 g (2.4 mmol in 5 ml DMF and the ether solution prepared above. Heat to 40 C. for 3 days. The product which contained no starting material by TLC was diluted with ether and extracted with 1 portion of 5% NaOH, followed by water and then brine. The ether layer was dried over Magnesium sulfate and isolated by removing ether by rotary evaporation (1.3 gms). The product may be further purified by chromatography (silica 99% ethyl acetate/1% NH4OH at 5 ml/min.). Isolated yield: 0.78 g (mass spec , and H1 NMR)

Step 11 ##STR480##

The product from step 10 (0.57 gms, 1.02 millimole fw 558.83 g/mole) and iodoethane (1.6 gms (10.02 mmilimoles)was place in 5 ml acetonitrile in a Fischer-Porter bottle and heated to 45 C. for 3 days. The solution was evaporated to dryness and redissolved in 5 mls of chloroform. Next ether was added to the chloroform solution and the resulting mixture was chilled. The desired product is isolated as a precipitate 0.7272 gms. Mass spec M-I=587.9, ¹ H NMR).

Example 1402 ##STR481## (4R-cis)-5-[[5-[4-[3,3-Dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4-hydroxy-1,1-dioxido-1-benzothiepin-5-yl]phenoxy]pentyl]thio]-1H-tetrazole-1-acetic acid

Step 1. Preparation of 4-fluoro-2-((4-methoxyphenyl)methyl)-phenol

To a stirred solution of 23.66 g of 95% sodium hydride (0.94 mol) in 600 mL of dry toluene was added 100.0 g of 4-fluorophenol (0.89 mol) at 0° C. The mixture was stirred at 90° C. for 1 hour until gas evolution stopped. The mixture was cooled down to room temperature and a solution of 139.71 g of 3-methoxybenzyl chloride (0.89 mol) in 400 mL of dry toluene was added. After refluxing for 24 hours, the mixture was cooled to room temperature and quenched with 500 mL of water. The organic layer was separated, dried over MgSO₄, and concentrated under high vacuum. The remaining starting materials were removed by distillation. The crude dark red oil was filtered through a layer of 1 L of silica gel with neat hexane to yield 53.00 g (25.6%) of the product as a pink solid: ¹ H NMR (CDCl₃) δ 3.79 (s, 3H), 3.90 (s, 2H), 4.58 (s, 1H), 6.70-6.74 (m, 1H), 6.79-6.88 (m, 4H), 7.11-7.16 (m, 2H).

Step 2. Preparation of 4-fluoro-2-((4-methoxyphenyl)methyl)-thiophenol

Step 2a. Preparation of Thiocarbamate

To a stirred solution of 50.00 g (215.30 mmol) of 4-fluoro-2-((4-methoxyphenyl)methyl)-phenol in 500 mL of dry DMF was added 11.20 g of 60% sodium hydride dispersion in mineral oil (279.90 mmol) at 2° C. The mixture was allowed to warm to room temperature and 26.61 g of dimethylthiocarbamoyl chloride (215.30 mmol) was added. The reaction mixture was stirred at room temperature overnight. The mixture was quenched with 100 mL of water in an ice bath. The solution was extracted with 500 mL of diethyl ether. The ether solution was washed with 500 mL of water and 500 mL of brine. The ether solution was dried over MgSO₄ and stripped to dryness. The crude product was filtered through a plug of 500 mL silica gel using 5% ethyl acetate/hexane to yield 48.00 g (69.8%) of the product as a pale white solid: ¹ H NMR (CDCl₃) δ 3.21 (s, 3H), 3.46 (s, 3H), 3.80 (s, 3H), 3.82 (s, 2H), 6.78-6.86 (m, 3H), 6.90-7.00 (m, 2H), 7.09 (d, J=8.7 Hz, 2H).

Step 2b. Rearrangement and Hydrolysis of Thiocarbamate to 4-fluoro-2-((4-methoxyphenyl)methyl)-thiophenol

A stirred solution of 48.00 g (150.29 mmol) of thiocarbamate (obtained from Step 2a) in 200 mL of diphenyl ether was refluxed at 270° C. overnight. The solution was cooled down to room temperature and filtered through 1 L of silica gel with 2 L of hexane to remove phenyl ether. The rearrangement product was washed with 5% ethyl acetate/hexane to give 46.00 g (95.8%) of the product as a pale yellow solid: ¹ H NMR (CDCl₃) δ 3.02 (s, 3H), 3.10 (s, 3H), 3.80 (s, 3H), 4.07 (s, 2H), 6.82-6.86 (m, 3H), 6.93 (dt, J=8.4 Hz, 2.7 Hz, 1H), 7.08 (d, J=8.7 Hz, 2H), 7.49 (dd, J=6.0 Hz, 8.7 Hz, 1H).

To a solution of 46.00 g (144.02 mmol) of the rearrangement product (above) in 200 mL of methanol and 200 mL of THF was added 17.28 g of NaOH (432.06 mmol). The mixture was refluxed under nitrogen overnight. The solvents were evaporated off and 200 mL of water was added. The aqueous solution was washed with 200 mL of diethyl ether twice and placed in an ice bath. The aqueous mixture was acidified to pH 6 with concentrated HCl solution. The solution was extracted with 300 mL of diethyl ether twice. The ether layers were combined, dried over MGSO₄ and stripped to dryness to afford 27.00 g (75.5%) of the product as a brown oil: ¹ H NMR (CDCl₃) δ 3.24 (s, 1H), 3.80 (s, 3H), 3.99 (s, 2H), 6.81-6.87 (m, 4H), 7.09 (d, J=8.7 Hz, 2H), 7.27-7.33 (m, 1H).

Step 3. Preparation of dibutyl cyclic sulfate

Step 3a. Preparation of 2,2-dibutyl-1,3-propanediol

To a stirred solution of di-butyl-diethylmalonate (Aldrich) (150 g, 0.55 mol in dry THF (700 ml) in an acetone/dry ice bath was added LAH (1 M THF) 662 ml (1.2 eq., 0.66 mol) dropwise maintaining the temperature between -20 to 0C. The reaction was stirred at RT overnight. The reaction was cooled to -20° C. and 40 ml of water, and 80 mL of 10% NaOH and 80 ml of water were added dropwise. The resulting suspension was filtered. The filtrate was dried over sodium sulphate and concentrated in vacuo to give diol 98.4 g (yield 95%) as an oil. MS spectra and proton and carbon NMR spectra were consistent with the product.

Step 3b. Preparation of dibutyl cyclic sulfite

A solution of 2,2-dibutyl-1,3-propanediol (103 g, 0.548 mol, obtained from Step 3a) and triethylamine (221 g, 2.19 mol) in anhydrous methylene chloride (500 ml) was stirred at 0° .C under nitrogen. To the mixture, thionyl chloride (97.8 g, 0.82 mol) was added dropwise and within 5 min the solution turned yellow and then black when the addition was completed within half an hour. The reaction mixture was stirred for 3 hrs. at 0° C. GC showed that there was no starting material left. The mixture was washed with ice water twice then with brine twice. The organic phase was dried over magnesium sulfate and concentrated under vacuum to give 128 g (100%) of the dibutyl cyclic sulfite as a black oil. Mass spectrum (MS) was consistent with the product.

Step 3c. Oxidation of dibutyl cyclic sulfite to dibutyl cyclic sulfate

To a solution of the dibutyl cyclic sulfite (127.5 g, 0.54 mol, obtained from Step 3b) in 600 ml acetonitrile and 500 ml of water cooled in an ice bath under nitrogen was added ruthenium (III) chloride (1 g) and sodium periodate (233 g, 1.08 mol). The reaction was stirred overnight and the color of the solution turned black. GC showed that there was no starting material left. The mixture was extracted with 300 ml of ether and the ether extract was washed three times with brine. The organic phase was dried over magnesium sulfate and passed through celite. The filtrate was concentrated under vacuum and to give 133 g (97.8%) of the dibutyl cyclic sulfate as an oil. Proton and carbon NMR and MS were consistent with the product.

Step 4. Preparation of aryl-3-hydroxypropylsulfide

To a stirred solution of 27.00 g (108.73 mmol) of 4-fluoro-2-((4-methoxyphenyl)methyl)thiophenol (obtained from Step 2) in 270 mL of diglyme was added 4.35 g of 60% sodium hydride dispersion in mineral oil (108.73 mmol) at 0° C. After gas evolution ceased, 29.94 g (119.60 mmol) of the dibutyl cyclic sulfate (obtained from Step 3c) was added at 0° C. and stirred for 10 minutes. The mixture was allowed to warm up to room temperature and stirred overnight. The solvent was evaporated and 200 mL of water was added. The solution was washed with 200 mL of diethyl ether and added 25 mL of concentrated sulfuric acid to make a 2.0 M solution that was refluxed overnight. The solution was extracted with ethyl acetate and the organic solution was dried over MgSO₄ and concentrated in vacuo. The crude aryl-3-hydroxypropylsulfide was purified by silica gel chromatography (Waters Prep 500) using 8% ethyl acetate/hexane to yield 33.00 g (72.5%) of the product as a light brown oil: ¹ H NMR (CDCl₃) δ 0.90 (t, J=7.1 Hz, 6H), 1.14-1.34 (m, 12H), 2.82 (s, 2H), 3.48 (s, 2H), 3.79 (s, 3H), 4.10 (s, 2H), 6.77-6.92 (m, 4H), 7.09 (d, J=8.7 Hz, 2H), 7.41 (dd, J=8.7 Hz, 5.7 Hz, 1H).

Step 5. Preparation of enantiomerically-enriched aryl-3-hydroxypropylsulfoxide

To a stirred solution of 20.00 g (47.78 mmol) of aryl-3-hydroxypropylsulfide (obtained from Step 4) in 1 L of methylene chloride was added 31.50 g of 96% (1R)-(-)-(8,8-dichloro-10-camphor-sulfonyl)oxaziridine (100.34 mmol, Aldrich) at 2° C. After all the oxaziridine dissolved the mixture was placed into a -30° C. freezer for 72 hours. The solvent was evaporated and the crude solid was washed with 1 L of hexane. The white solid was filtered off and the hexane solution was concentrated in vacuo. The crude oil was purified on a silica gel column (Waters Prep 500) using 15% ethyl acetate/hexane to afford 19.00 g (95%) of the enantiomerically-enriched aryl-3-hydroxypropylsulfoxide as a colorless oil: ¹ H NMR (CDCl₃) δ 0.82-0.98 (m, 6H), 1.16-1.32 (m, 12H), 2.29 (d, J=13.8 Hz, 1H), 2.77 (d, J=13.5 Hz, 1H), 3.45 (d, J=12.3 Hz, 1H), 3.69 (d, J=12.3 Hz, 1H), 3.79 (s, 3H), 4.02 (q, J=15.6 Hz, 1H), 6.83-6.93 (m, 3H), 7.00 (d, J=8.1 Hz, 2H), 7.18-7.23 (m, 1H), 7.99-8.04 (m, 1H). Enantiomeric excess was determined by chiral HPLC on a (R,R)-Whelk-O column using 5% ethanol/hexane as the eluent. It showed to be 78% e.e. with the first eluting peak as the major product.

Step 6. Preparation of enantiomerically-enriched aryl-3-propanalsulfoxide

To a stirred solution of 13.27 g of triethylamine (131.16 mmol, Aldrich) in 200 mL dimethyl sulfoxide were added 19.00 g (43.72 mmol) of enantiomerically-enriched aryl-3-hydroxypropylsulfoxide (obtained from Step 5) and 20.96 g of sulfur trioxide-pyridine (131.16 mmol, Aldrich) at room temperature. After the mixture was stirred at room temperature for 48 hours, 500 mL of water was added to the mixture and stirred vigorously. The mixture was then extracted with 500 mL of ethyl acetate twice. The ethyl acetate layer was separated, dried over MgSO₄, and concentrated in vacuo. The crude oil was filtered through 500 mL of silica gel using 15% ethyl acetate/hexane to give 17.30 g (91%) of the enantiomerically-enriched aryl-3-propanalsulfoxide as a light orange oil: ¹ H NMR (CDCl₃) δ 0.85-0.95 (m, 6H), 1.11-1.17 (m, 4H), 1.21-1.39 (m, 4H), 1.59-1.76 (m, 4H), 1.89-1.99 (m, 1H), 2.57 (d, J=14.1 Hz, 1H), 2.91 (d, J=13.8 Hz, 1H), 3.79 (s, 3H), 3.97 (d, J=15.9 Hz, 1H), 4,12 (d, J=15.9 Hz, 1H), 6.84-6.89 (m, 3H), 7.03 (d, J=8.4 Hz, 2H), 7.19 (dt, J=8.4 Hz, 2.4 Hz, 1H), 8.02 (dd, J=8.7 Hz, 5.7 Hz, 1H), 9.49 (s, 1H).

Step 7. Preparation of the enantiomerically-enriched tetrahydrobenzothiepine-1-oxide (4R,5R)

To a stirred solution of 17.30 g (39.99 mmol) of enantiomerically-enriched aryl-3-propanalsulfoxide (obtained from Step 6) in 300 mL of dry THF at -15° C. was added 48 mL of 1.0 M potassium t-butoxide in THF (1.2 equivalents) under nitrogen. The solution was stirred at -15° C. for 4 hours. The solution was then quenched with 100 mL of water and neutralized with 4 mL of concentrated HCl solution at 0° C. The THF layer was separated, dried over MgSO₄, and concentrated in vacuo. The enantiomerically-enriched tetrahydrobenzothiepine-1-oxide (4R,5R) was purified by silica gel chromatography (Waters Prep 500) using 15% ethyl acetate/hexane to give 13.44 g (77.7%) of the product as a white solid: ¹ H NMR (CDCl₃) δ 0.87-0.97 (m, 6H), 1.16-1.32 (m, 4H), 1.34-1.48 (m, 4H), 1.50-1.69 (m, 4H), 1.86-1.96 (m, 1H), 2.88 (d, J=13.0 Hz, 1H), 3.00 (d, J=13.0 Hz, 1H), 3.85 (s, 3H), 4.00 (s, 1H), 4.48 (s, 1H), 6.52 (dd, J=9.9 Hz, 2.4 Hz, 1H), 6.94 (d, J=9 Hz, 2H), 7.13 (dt, J=8.4 Hz, 2.4 Hz, 1H), 7.38 (d, J=8.7 Hz, 2H), 7.82 (dd, J=8.7 Hz, 5.7 Hz, 1H).

Step 8. Preparation of enantiomerically-enriched tetrahydrobenzothiepine-1,1-dioxide (4R,5R)

To a stirred solution of 13.44 g (31.07 mmol) of enantiomerically-enriched tetrahydrobenzothiepine-1-oxide (obtained from Step 7) in 150 mL of methylene chloride was added 9.46 g of 68% m-chloroperoxybenzoic acid (37.28 mmol, Sigma) at 0° C. After stirring at 0° C. for 2 hours, the mixture was allowed to warm up to room temperature and stirred for 4 hours. 50 mL of saturated Na₂ SO₃ was added into the mixture and stirred for 30 minutes. The solution was then neutralized with 50 mL of saturated NaHCO₃ solution. The methylene chloride layer was separated, dried over MgSO₄, and concentrated in vacuo to give 13.00 g (97.5%) of the enantiomerically-enriched tetrahydrobenzothiepine-1,1-dioxide (4R,5R) as a light yellow solid: ¹ H NMR (CDCl₃) δ 0.89-0.95 (m, 6H), 1.09-1.42 (m, 12H), 2.16-2.26 (m, 1H), 3.14 (q, J=15.6 Hz, 1H), 3.87 (s, 3H), 4.18 (s, 1H), 5.48 (s, 1H), 6.54 (dd, J=10.2 Hz, 2.4 Hz, 1H), 6.96-7.07 (m, 3H), 7.40 (d, J=8.1 Hz, 2H), 8.11 (dd, J=8.6 Hz, 5.9 Hz, 1H).

Step 9. Preparation of enantiomerically-enriched 7-(dimethylamino)tetrahydrobenzothiepine-1,1-dioxide (4R,5R)

To a solution of 13.00 g (28.98 mmol) of enantiomerically-enriched tetrahydrobenzothiepine-1,1-dioxide (obtained from Step 8) in 73 mL of dimethylamine (2.0 M in THF, 146 mmol) in a Parr Reactor was added about 20 mL of neat dimethylamine. The mixture was sealed and stirred at 110° C. overnight, and cooled to ambient temperature. The excess dimethylamine was evaporated. The crude oil was dissolved in 200 mL of ethyl acetate and washed with 100 mL of water, dried over MgSO₄ and concentrated in vacuo. Purification on a silica gel column (Waters Prep 500) using 20% ethyl acetate/hexane gave 12.43 g (90.5%) of the enantiomerically-enriched 7-(dimethylamino)tetrahydrobenzothiepine-1,1-dioxide (4R,5R) as a colorless solid: ¹ H NMR (CDCl₃) δ 0.87-0.93 (m, 6H), 1.10-1.68 (m, 12H), 2.17-2.25 (m, 1H), 2.81 (s, 6H), 2.99 (d, J=15.3 Hz, 1H), 3.15 (d, J=15.3 Hz, 1H), 3.84 (s, 3H), 4.11 (d, J=7.5 Hz, 1H), 5.49 (s, 1H), 5.99 (d, J=2.4 Hz, 1H), 6.51 (dd, J=8.7 Hz, 2.4 Hz, 1H), 6.94 (d, J=8.7 Hz, 2H), 7.42 (d, J=8.4 Hz, 2H), 7.90 (d, J=8.7 Hz, 1H). The product was determined to have 78% e.e. by chiral HPLC on a Chiralpak AD column using 5% ethanol/hexane as the eluent. Recrystallization of this solid from ethyl acetate/hexane gave 1.70 g of the racemic product. The remaining solution was concentrated and recrystallized to give 9.8 g of colorless solid. Enantiomeric excess of this solid was determined by chiral HPLC on a Chiralpak AD column using 5% ethanol/hexane as the eluent. It showed to have 96% e.e with the first eluting peak as the major product.

Step 10: Demethylation of 5-(4'-methoxyphenyl)-7-(dimethylamino)tetrahydrobenzothiepine-1,1-dioxide (4R,5R)

To a solution of 47 g (99 mmol) of enantiomeric-enriched (dimethylamino)tetrahydrobenzothiepine-1,1-dioxide (obtained from Step 9) in 500 mL of methylene chloride at -10° C. was added dropwise a solution of boron tribromide (297 mL, 1M in methylene chloride, 297 mmol), and the resulting solution was stirred cold (-5° C. to 0° C.) for 1 hour or until the reaction was complete. The reaction was cooled in an acetone-dry ice bath at -10° C., and slowly quenched with 300 mL of water. The mixture was warmed to 10° C., and further diluted with 300 mL of saturated sodium bicarbonate solution to neutralize the mixture. The aqueous layer was separated and extracted with 300 mL of methylene chloride, and the combined extracts were washed with 200 mL of water, brine, dried over MgSO₄ and concentrated in vacuo. The residue was dissolved in 500 mL of ethyl acetate and stirred with 50 mL of glacial acetic acid for 30 minutes at ambient temperature. The mixture was washed twice with 200 mL of water, 200 mL of brine, dried over MgSO₄ and concentrated in vacuo to give the crude 4-hydroxyphenyl intermediate. The solid residue was recrystallized from methylene chloride to give 37.5 g (82%) of the desired 5-(4'-hydroxyphenyl)-7-(dimethylamino)tetrahydrobenzothiepine-1,1-dioxide as a white solid: ¹ H NMR (CDCl₃) δ 0.84-0.97 (m, 6H), 1.1-1.5 (m, 10H), 1.57-1.72 (m, 1H), 2.14-2.28 (m, 1H), 2.83 (s, 6H), 3.00 (d, J=15.3 Hz, 1H), 3.16 (d, J=15.3 Hz, 1H), 4.11 (s, 2H), 5.48 (s, 1H), 6.02 (d, J=2.4 Hz, 1H), 6.55 (dd, J=9, 2.4 Hz, 1H), 6.88 (d, 8,7 Hz, 2H), 7.38 (d, J=8.7 Hz, 2H), 7.91 (d, J=9 Hz, 2H).

Alternatively, enantiomeric-enriched 5-(4'-hydroxyphenyl)-7-(dimethylamino)tetrahydrobenzothiepine-1,1-dioxide, the intermediate just described, can be prepared via non-enantioselective synthesis followed by chiral chromatography separation. Oxidation of aryl-3-hydroxypropylsulfide (obtained from Step 4) with m-chloroperbenzoic acid (under the similar conditions as in Step 8, but with 2.2 equivalent of m-CPBA) gave the racemic sulfone intermediate. The sulfone was carried through the synthetic sequences (under the same conditions as in Step 7 and Step 9) to give the racemic 5-(4'-hydroxyphenyl)-7-(dimethylamino)tetrahydrobenzothiepine-1,1-dioxide. The two enantiomers were further separated into the desired enantiomeric-enriched 5-(4'-hydroxyphenyl)-7-(dimethylamino)tetrahydrobenzothiepine-1,1-dioxide by appropriate chiral chromatographic purification.

Step 11: Preparation of ester intermediate

To a solution of 1.0 g (2.18 mmol) of 5-(4'-hydroxyphenyl)-7-(dimethylamino)tetrahydrobenzothiepine-1,1-dioxide (obtained from Step 10) in 10 mL dimethylformamide was added 60 mg (2.38 mmol) of 95% sodium hydride and stirred for 15 minutes. To the reaction mixture was added 400 μL (2.52 mmol) of benzyl 2-bromoacetate and stirred for two hours. Water was added to the reaction mixture, extracted with ethyl acetate, washed with brine, dried over magnesium sulfate, filtered and the solvent evaporated to afford 1.30 g (98%) of the ester intermediate: ¹ H NMR (CDCl₃) δ0.88-0.94 (m, 6H), 1.13-1.46 (m, 10H), 1.60-1.64 (m, 1H), 2.20-2.24 (m, 1H), 2.81 (s, 6H), 3.00 (d, J=15.1 Hz, 1H), 3.16 (t, J=15.1 Hz, 1H), 4.11 (s, 1H), 5.26 (s, 2H), 5.49 (s, 1H), 6.04 (d, J=2.4 Hz, 1H), 6.63 (dd, J=8.9, 2.4 Hz, 1H), 6.95 (d, J=8.7 Hz, 2H), 7.37 (s, 5H), 7.42 (d, J=8.5 Hz, 2H), 7.93 (d, J=8.9 Hz, 1H).

Step 12: Preparation of acid

A solution of 1.30 g (2.14 mmol) of ester intermediate (obtained from Step 1) in 40 mL ethanol with 10% palladium on carbon was placed under an atmosphere of hydrogen gas (40 psi) for three hours. The reaction mixture was filtered through celite and the solvent was evaporated to afford the desired title compound as a white solid: mp 119-123° C.; ¹ H NMR (CDCl₃) δ 0.89-0.94 (m, 6H), 1.19-1.43 (m, 10H), 1.61-1.65 (m, 1H), 2.17-2.21 (m, 1H), 2.85 (s, 6H), 3.02 (d, J=15.1 Hz, 1H), 3.17 (t, J=14.9 Hz, 1H), 4.12 (s, 1H), 4.72 (s, 2H), 5.51 (s, 1H), 6.17 (s, 1H), 6.74 (d, J=9.1 Hz, 1H), 6.99 (d, J=8.3 Hz, 2H), 7.46 (d, J=8.5 Hz, 2H), 7.97 (d, J=8.7 Hz, 1H). HRMS. Calc'd for C₂₈ H₄₀ NO₆ S: 518.2576. Found: 518.2599.

Example 1403 ##STR482## (4R-cis)-N-[[4-[3,3-Dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4-hydroxy-1,1-dioxido-1-benzothiepin-5-yl]phenoxyacetyl]glycine

Step 1: Preparation of glycine ester intermediate

To a solution of 6.4 g (13.9 mmol) of 5-(4'-hydroxyphenyl)-7-(dimethylamino)tetrahydrobenzo-thiepine-1,1-dioxide (obtained from Example 1402, Step 10) and 2.9 g (21.0 mmol) of potassium carbonate in 100 ml of acetone was added 3.8 g (21.0 mmol) of N-(chloroacetyl)glycine ethyl ester and 50 mg (0.14 mmol) of tetrabutylammonium iodide. The reaction was heated to reflux for 2 days, cooled to ambient temperature and stirred for 20 hours, then partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over MgSO₄, and concentrated in vacuo. Purification by silica gel chromatography (Waters Prep-500) using 50% ethyl acetate/hexanes afforded 7.5 g (90%) of glycine ester intermediate as a white foam: ¹ H NMR (CDCl₃) δ 0.86-0.98 (m, 6H), 1.04-1.56 (m, 13H), 1.58-1.71 (m, 1H), 2.14-2.29 (m, 1H), 2.73 (s, 6H), 3.08 (AB_(q), J_(AB) =15.3 Hz, J=48.9 Hz, 2H), 4.06-4.19 (m, 6H), 4.25 (q, J=7.0 Hz, 2H), 4.57 (s, 2H), 5.50 (s, 1H), 5.98 (s, 1H), 6.56 (d, J=8.6 Hz, 1H), 6.98 (d, J=8.5 Hz, 2H), 7.17 (s, 1H), 7.47 (d, J=8.3 Hz, 2H), 7.91 (d, J=8.7 Hz, 1H).

Step 2: Preparation of acid

A solution of 7.3 g (12.1 mmol) of glycine ester intermediate (obtained from Step 1) and 1.5 g LiOH.H₂ O (36.3 mmol) in 60 mL of THF and 60 mL of water was heated to 45° C. for 2 hours. This was then cooled to ambient temperature, acidified with 1 N HCl and partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over MgSO₄, and concentrated in vacuo. Purification by recrystallization from ethyl acetate gave 5.45 g (78%) of the desired title compound as a white crystalline solid: mp 149-150° C.; ¹ H NMR (CD₃ OD) δ 0.88-0.98 (m, 6H), 1.06-1.56 (m, 10H), 1.70-1.84 (m, 1H), 2.06-2.20 (m, 1H), 2.79 (s, 6H), 3.11 (AB_(q), J_(AB) =15.3 Hz, J=21.6 Hz, 2H), 4.01 (s, 2H), 4.07 (s, 1H), 4.61 (s, 2H), 5.31 (s, 1H), 6.04 (s, 1H), 6.57 (d, J=9.0 Hz, 1H), 7.08 (d, J=7.8 Hz, 2H), 7.44 (d, J=8.1 Hz, 2H), 7.76 (d, J=9.0 Hz, 1H), 8.42 (m, 1H). HRMS(ES+) Calc'd for C₃₀ H₄₂ N₂ O₇ S: 575.2712. Found: 575.2790. Anal.

Calc'd for: C₃₀ H₄₂ N₂ O₇ S C, 62.69; H, 7.37; N, 4.87. Found: C, 62.87; H, 7.56; N, 4.87.

Example 1403 ##STR483## (4R-cis)-N-[[4-[3,3-Dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4-hydroxy-1,1-dioxido-1-benzothiepin-5-yl]phenoxyacetyl]glycine

Step 1: Preparation of glycine ester intermediate

To a solution of 6.4 g (13.9 mmol) of 5-(4'-hydroxyphenyl)-7-(dimethylamino)tetrahydrobenzothiepine-1,1-dioxide (obtained from Example 1402, Step 10) and 2.9 g (21.0 mmol) of potassium carbonate in 100 ml of acetone was added 3.8 g (21.0 mmol) of N-(chloroacetyl)glycine ethyl ester and 50 mg (0.14 mmol) of tetrabutylammonium iodide. The reaction was heated to reflux for 2 days, cooled to ambient temperature and stirred for 20 hours, then partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over MgSO₄, and concentrated in vacuo. Purification by silica gel chromatography (Waters Prep-500) using 50% ethyl acetate/hexanes afforded 7.5 g (90%) of glycine ester intermediate as a white foam: ¹ H NMR (CDCl) δ 0.86-0.98 (m, 6H), 1.04-1.56 (m, 13H), 1.58-1.71 (m, 1H), 2.14-2.29 (m, 1H), 2.73 (s, 6H), 3.08 (AB_(q), J_(AB) =15.3 Hz, J=48.9 Hz, 2 H), 4.06-4.19 (m, 6H), 4.25 (q, J=7.0 Hz, 2H), 4.57 (s, 2H), 5.50 (s, 1H), 5.98 (s, 1H), 6.56 (d, J=8.6 Hz, 1H), 6.98 (d, J=8.5 Hz, 2H), 7.17 (s, 1H), 7.47 (d, J=8.3 Hz, 2H), 7.91 (d, J=8.7 Hz, 1H).

Step 2: Preparation of acid

A solution of 7.3 g (12.1 mmol) of glycine ester intermediate (obtained from Step 1) and 1.5 g LiOH.H₂ O (36.3 mmol) in 60 mL of THF and 60 mL of water was heated to 45° C. for 2 hours. This was then cooled to ambient temperature, acidified with 1 N HCl and partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over MgSO₄, and concentrated in vacuo. Purification by recrystallization from ethyl acetate gave 5.45 g (78%) of the desired title compound as a white crystalline solid: mp 149-150° C.; ¹ H NMR (CD₃ OD) δ 0.88-0.98 (m, 6H), 1.06-1.56 (m, 10H), 1.70-1.84 (m, 1H), 2.06-2.20 (m, 1H), 2.79 (s, 6H), 3.11 (AB_(q), J_(AB) =15.3 Hz, J=21.6 Hz, 2H), 4.01 (s, 2H), 4.07 (s, 1H), 4.61 (s, 2H), 5.31 (s, 1H), 6.04 (s, 1H), 6.57 (d, J=9.0 Hz, 1H), 7.08 (d, J=7.8 Hz, 2H), 7.44 (d, J=8.1 Hz, 2H), 7.76 (d, J=9.0 Hz, 1H), 8.42 (m, 1H). HRMS(ES+) Calc'd for C₃₀ H₄₂ N₂ O₇ S: 575.2712. Found: 575.2790. Anal. Calc'd for: C₃₀ H₄₂ N₂ O₇ S C, 62.69; H, 7.37; N, 4.87. Found: C, 62.87; H, 7.56; N, 4.87.

Example 1404 ##STR484## (4R-cis)-5-[4-[3,3-Dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4-hydroxy-1,1-dioxido-1-benzothiepin-5-yl]phenoxy]pentanoic acid

Step 1: Preparation of ester intermediate

A solution of 5-(4'-hydroxyphenyl)-7-(dimethylamino)tetrahydrobenzothiepine-1,1-dioxide (1.0 g, 2.2 mmol, obtained from Example 1402, Step 10) in acetone (10 mL) at 25° C. under N₂ was treated with powdered K₂ CO₃ (0.45 g, 3.3 mmol, 1.5 eq.), benzyl 5-bromovalerate (0.88 g, 3.3 mmol, 1.5 eq.) and a catalytic amount of tetra-n-butylammonium iodide (2 mg), and the resulting solution was stirred at 65° C. for 24 hours. The pale amber slurry was cooled to 25° C. and was concentrated in vacuo to provide a yellow residue. Purification by flash chromatography (2.4×30 cm silica, 20-40% EtOAc/hexane) afforded the ester intermediate (1.2 g, 86%) as a colorless oil: ¹ H NMR (CDCl₃) δ 0.91 (m, 6H), 1.11-1.47 (br m, 10H), 1.64 (m, 1H), 1.86 (m, 2H), 2.21 (m, 1H), 2.47 (m, 2H), 2.81 (s, 6H), 3.05 (ABq, J=15.1 Hz, J=47.7 Hz, 2H), 4.10 (d, J=7.9 Hz, 1H), 5.13 (s, 2H), 5.47 (s, 1H), 6.00 (d, J=2.5 Hz, 1H), 6.50 (dd, J=8.9, 2.5 Hz, 1H), 6.91 (d, J=8.7 Hz, 2H), 7.36 (m, 5H), 7.40 (d, J=8.5 Hz, 2H), 7.86 (d, J=8.9 Hz, 1H); HRMS. Calc'd for C₃₈ H₅₁ NO₆ S: 650.3515. Found: 650.3473.

Step 2: Preparation of acid

A solution of the ester intermediate (0.99 g, 1.5 mmol, obtained from Step 1) in ethanol (7.5 mL) at 25° C. was treated with 5% palladium on carbon (0.15 g, 10 wt %) then stirred under an atmosphere (1 atm) of H₂ via hydrogen balloon. Every 10 min, hydrogen gas was bubbled through the slurry for 1 min, for a total reaction time of 4 hours. The slurry was placed under an atmosphere of N₂ and nitrogen was bubbled through the reaction mixture for 10 min. The mixture was filtered through a plug of Celite® (10 g) and concentrated in vacuo to give a white foam. Purification by flash chromatography (2.6×25 cm silica, 1.5% EtOH/CH₂ Cl₂) afforded the desired title compound (0.54 g, 63%) as a white foam: mp: 76-79° C.; ¹ H NMR (CDCl₃) δ 0.90 (m, 6H), 1.10-1.46 (br m, 10H), 1.62 (m, 1H), 1.87 (m, 4H), 2.20 (m, 1H), 2.45 (m, 2H), 2.81 (s, 6H), 3.05 (ABq, J=15.1 Hz, J=49.7 Hz, 2H), 4.00 (s, 2H), 4.09 (s, 1H), 5.45 (s, 1H), 5.99 (d, J=2.4 Hz, 1H), 6.48 (dd, J=8.9, 2.4 Hz, 1H), 6.91 (d, J=8.7 Hz, 2H), 7.39 (m, 5H), 7. 39 (d, J=8.3 Hz, 2H), 7.84 (d, J=8.9 Hz, 1H); HRMS. Calc'd for C₃₁ H₄₅ NO₆ S: 560.3046. Found: 560.3043.

Example 1405 ##STR485## (4R-cis)-4-[4-[3,3-Dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4-hydroxy-1,1-dioxido-1-benzothiepin-5-yl]phenoxy-1-butanesulfonamide

Step 1: Preparation of sulfonic acid intermediate

A solution of 7.4 g (16.1 mmol) of 5-(4'-hydroxyphenyl)-7-(dimethylamino)tetrahydrobenzothiepine-1,1-dioxide (obtained from Example 1402, Step 10) in acetone (35 mL) at 25° C. under N₂ was treated with powdered potassium carbonate (3.3 g, 24.1 mmol, 1.5 equiv.) and 1,4-butane sultone (2.5 mL, 24.1 mmol, 1.5 equiv.) and stirred and heated at 65° C. for 64 h. The solution was allowed to cool to 25° C. and quenched by the addition of water (50 mL), until a homogeneous mixture was obtained. The clear and colorless solution was added dropwise to a 4 N HCl solution cooled to 0° C. over a 30 min period. The mixture was vigorously stirred for 4 h then allowed to warm to ambient temperature and stirred for an additional 16 h. The resultant white precipitate was filtered and washed with water and dried in vacuo to provide 8.8 g (92%) of the desired sulfonic acid as a white solid. A portion of the white solid was recrystallized from CH₃ CN/hexane to give the desired sulfonic acid as colorless needles: mp 229-236° C. (decomposed); ¹ H NMR (DMSO-d₆) δ 0.82 (m, 6H), 1.02-1.33 (br m, 10H), 1.59 (m, 1H), 1.73 (m, 4H), 2.00 (s, 1H), 2.48 (m, 2H), 2.71 (s, 611), 2.98 (s, 1H), 3.86 (s, 1H), 3.93 (m, 2H), 5.08 (s, 1H), 5.89 (s, 1H), 6.52 (dd, J=8.9, 2.4 Hz, 1H), 6.92 (d, J=8.3 Hz, 2H), 7.29 (d, J=8.1 Hz, 2H), 7.60 (d, J=8.9 Hz, 1H); Anal. Calc'd for C₃₀ H₄₅ NO₇ S₂ : C, 60.48; H, 7.61; N, 2.35. Found: C, 60.53; H, 7.70; N, 2.42.

Step 2: Preparation of 7-(dimethylamino)-benzothiepin-5-yl]phenoxy-1-butanesulfonamide

To a solution of 1.12 g (1.88 mmol) of the sulfonic acid (obtained from Step 1) in 10 mL CH₂ Cl₂ was added 785 mg (3.77 mmol) PCl₅ and stirred for 1 hour. Water was added and the mixture was extracted and washed with brine. Dried with MgSO₄, filtered and solvent evaporated. To the residue was added 30 mL of 0.5M NH₃ in dioxane and stirred 16 hours. The precipitate was filtered and the solvent evaporated. The residue was purified by MPLC (33% EtOAc in hexane) to afford the desired title compound as a beige solid (125 mg, 11%): mp 108-110° C.; ¹ H NMR (CDCl₃) δ 0.85-0.93 (m, 6H), 1.13-1.59 (m, 10H), 1.60-1.67 (m, 1H), 1.94-2.20 (m, 5H), 2.82 (s, 6H), 2.99 (d, J=15.3 Hz, 1H), 3.15 (t, J=15.3 Hz, 1H), 3.23 (t, J=7.7 Hz, 2H), 4.03 (t, J=5.8 Hz, 2H), 4.08-4.10 (m, 1H), 4.79 (s, 2H), 5.47 (s, 1H), 6.02 (d, J=2.4 Hz, 1H), 6.52 (dd, J=8.9, 2.6 Hz, 1H), 6.91 (d, J=8.9 Hz, 2H), 7.41 (d, J=8.5 Hz, 2H), 7.89 (d, J=8.9 Hz, 1H). HRMS. Calc'd for C₃₀ H₄₇ N₂ O₆ S₂ : 595.2876. Found: 595.2874.

Example 1406 ##STR486## (4R-cis)-1-[3-[4-[3,3-Dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4-hydroxy-1,1-dioxido-1-benzothiepin-5-yl]phenoxy]propyl]-4-aza-1-azoniabicyclo[2.2.2]octane, methanesulfonate (salt)

Step 1: Preparation of dimesylate intermediate

To a cooled (-20° C.) solution of 5.0 g (65.7 mmol) of 1,3-propanediol in 50 mL of triethylamine and 200 mL of methylene chloride was added 15.8 g (137.9 mmol) of methanesulfonyl chloride. The mixture was stirred for 30 minutes, then warmed to ambient temperature and partitioned between ethyl acetate and 1N HCl. The organic layer was washed with brine, dried over MgSO₄, and concentrated in vacuo to give 13.5 g (89%) of dimesylate intermediate as a clear yellowish oil: ¹ H NMR (CDCl₃) δ 2.12 (quintet, J=4.5 Hz, 4H), 3.58 (s, 6H), 4.38 (t, J=5.4 Hz)

Step 2: Preparation of propyl mesylate intermediate

To a solution of 2.4 g (5.2 mmol) of 5-(4'-hydroxyphenyl)-7-(dimethylamino)tetrahydrobenzothiepine-1,1-dioxide (obtained from Example 1402, Step 10) and 6.0 g (26.1 mmol) of dimesylate intermediate (obtained from Step 1) in 50 mL of acetone was added 3.6 g (26.1 mmol) of K₂ CO₃. The reaction was heated to reflux overnight then cooled to ambient temperature and concentrated in vacuo. The residue was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over MgSO₄, and concentrated in vacuo. Purification by silica gel chromatography (Waters-Prep 500) using 36% ethyl acetate/hexanes afforded 2.8 g (90%) of the propyl mesylate intermediate as a white foam: ¹ H NMR (CDCl₃) δ 0.86-0.95 (m, 6H), 1.06-1.52 (m, 10H), 1.57-1.70 (m, 1H), 2.14-2.32 (m, 3H), 2.84 (s, 6H), 3.02 (s, 3H), 3.08 (AB_(q), J_(AB) =15.0 Hz, J=46.9 Hz, 4.09-4.18 (m, 3H), 4.48 (t, J=6.0 Hz, 2H), 5.49 (s, 1H), 6.11 (s, 1H), 6.65 (d, J=8.7 Hz, 1H), 6.94(d, J=8.6 Hz, 2H), 7.43 (d, J=8.5 Hz, 2H), 7.94 (d, J=8.9 Hz, 1H).

Step 3: Preparation of quaternary salt

To a solution of 1.2 g (2.0 mmol) of propyl mesylate intermediate (obtained from Step 2) in 20 ml of acetonitrile was added 0.3 g (2.9 mmol) of 1,4-diazabicyclo[2.2.2]octane (DABCO). The reaction mixture was stirred at 60° C. for three hours, then cooled to ambient temperature and concentrated in vacuo. Purification by trituration with methylene chloride/ethyl ether gave 1.3 g (91%) of the desired title compound as a white solid: mp. (dec) 230-235° C.; ¹ H NMR (CDCl₃) δ 0.86-0.95 (m, 6H), 1.04-1.52 (m, 10H), 1.57-1.70 (m, 1H), 2.12-2.25 (m, 3H), 2.28-2.39 (m, 2H), 2.83 (s, 6H), 3.04 (s, 3H), 3.09 (AB_(q), J_(AB) =15.6 Hz, J=42.2 Hz, 2H) 3.22-3.32 (m, 6H), 3.56-3.66 (m, 6H), 3.73-3.83 (m, 2H), 4.06-4.17 9m, 3H), 5.47 (s, 1H), 5.97 (s, 1H), 6.51 (d, J=8.6 Hz, 1H), 6.90(d, J=8.6 Hz, 2H), 7.41 (d, J=8.7 Hz, 2H), 7.89 (d, J=8.9 Hz, 1H). MS (ES+) m/e 612.4. HRMS (ES+) Calc'd for C₃₅ H₅₄ N₃ O₄ S⁺ : 612.3835. Found: 612.3840.

Example 1407 ##STR487## (4R-cis)-1-[3-[4-[3,3-Dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4-hydroxy-1,1-dioxido-1-benzothiepin-5-yl]phenoxy]propyl]-4-aza-1-azoniabicyclo[2.2.2]octane,4-methylbenzenesulfonate (salt)

Step 1: Preparation of propyl tosylate intermediate

A solution of 5-(4'-hydroxyphenyl)-7-(dimethylamino)tetrahydrobenzothiepine-1,1-dioxide (5.0 g, 10.9 mmol, obtained from Example 1402, Step 10) in acetone (100 mL) at 25° C. under N₂ was treated with powdered K₂ CO₃ (3.8 g, 27.2 mmol, 2.5 eq.) and 1,3-propanediol di-p-tosylate (13.0 g, 32.6 mmol, 3.0 eq.), and the resulting mixture was stirred at 65° C. for 21 hours. The cream-colored slurry was cooled to 25° C. and was filtered through a sintered glass funnel. The filtrate was concentrated and the residue was dissolved in EtOAc (150 mL). The organic layer was washed with saturated aqueous NaHCO₃ (2×150 mL) and saturated aqueous NaCl (2×150 mL), and was dried (MgSO₄) and concentrated in vacuo to provide a pale orange oil. Purification by flash chromatography (4.4×35 cm silica, 20-30% EtOAc/hexane) afforded the propyl tosylate intermediate (6.0 g, 80%) as a white foam: ¹ H NMR (CDCl₃) δ 0.91 (m, 6H), 1.11-1.47 (br m, 10H), 1.63 (m, 1H), 2.14 (m, 2H), 2.21 (m, 1H), 2.41 (s, 3H), 2.81 (s, 6H), 3.06 (ABq, J=15.1 Hz, J=49.0 Hz, 2H), 4.01 (t, J=5.3 Hz, 2H), 4.10 (m, 1H), 4.26 (t, J=5.9 Hz, 2H), 5.29 (s, 1H), 5.48 (s, 1H), 5.98 (s, 1H), 6.51 (dd, J=8.9, 1.8 Hz, 1H), 6.83 (d, J=8.4 Hz, 2H), 7.30 (d, J=8.1 Hz, 2H), 7.39 (d, J=8.3 Hz, 2H), 7.78 (d, J=8.3 Hz, 2H), 7.88 (d, J=8.9 Hz, 1H).

Step 2: Preparation of quaternary salt

A solution of the propyl tosylate intermediate (1.05 g, 1.56 mmol, obtained from Step 1) in acetonitrile (15 mL) at 25° C. under N₂ was treated with diazabicyclo[2.2.2]octane (DABCO, 0.26 g, 2.34 mmol, 1.5 eq.) and stirred at 50° C. for 6 hours, then at 25° C. for 14 hours. The pale amber solution was cooled to 25° C. and concentrated in vacuo to provide an amber oil. The residue was dissolved in a minimal amount of CH₂ Cl₂ (5 mL) and diluted with Et₂ O (100 mL) while vigorously stirring for 4 hours, during which time a white solid precipitated. The white solid was collected (Et₂ O wash) to give the desired title compound (1.11 g, 90%) as a white amorphous solid: mp 136.5-142° C. (decomposed); ¹ H NMR (CDCl₃) δ 0.89 (m, 6H), 1.12-1.43 (br m, 9H), 1.61 (m, 1H), 1.65 (m, 1H), 2.18 (m, 1H), 2.22 (m, 2H), 2.27 (s, 3H), 2.78 (s, 6H), 3.07 (ABq, J=15.1 Hz, J=39.5 Hz, 2H), 3.49 (br s, 6H), 3.68 (m, 1H), 3.74 (br s, 6H), 3.96 (br s, 2H), 4.09 (d, J=7.3 Hz, 1H), 5.46 (s, 1H), 5.96 (d, J=2.4 Hz, 1H), 6.49 (dd, J=8.9, 2.4 Hz, 1H), 6.83 (d, J=8.5 Hz, 2H), 7.11 (d, J=8.1 Hz, 2H), 7.40 (d, J=8.3 Hz, 2H), 7.74 (d, J=8.1 Hz, 2H), 7.87 (d, J=8.9 Hz, 1H); HRMS. Calc'd for C₃₅ H₅₄ N₃ O₄ S: 612.3835. Found: 612.3832.

Example 1408 ##STR488## (4R-cis)-1-[4-[4-[3,3-Dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4-hydroxy-1,1-dioxido-1-benzothiepin-5-yl]phenoxy]butyl]-4-aza-1-azoniabicyclo[2.2.2]octanemethanesulfonate (salt)

Step 1: Preparation of butyl mesylate intermediate

A mixture of 1.00 g (2.18 mmol) of 5-(4'-hydroxyphenyl)-7-(dimethylamino)tetrahydrobenzothiepine-1,1-dioxide (obtained from Example 1402, Step 10), 2.68 g (10.88 mmol) of busulfan, and 1.50 g (10.88 mmol) of potassium carbonate in 20 mL of acetone was stirred at reflux overnight. The mixture was concentrated in vacuo and the crude was dissolved in 30 mL of ethyl acetate. The insoluble solid was filtered off and the filtrate was concentrated in vacuo. The resulting white foam was chromatographed through silica gel column, and eluted with 30% ethyl acetate/hexane to give 1.02 g (77%) of butyl mesylate intermediate as a white solid: ¹ H NMR (CDCl₃) δ 0.90 (m, 6H), 1.20-1.67 (m, 12H), 1.98 (m, 4H), 2.22 (m, 1H), 2.83 (s, 6H), 3.04 (s, 3H), 3.08 (ABq, 2H), 4.05 (t, J=5.55 Hz, 2H), 4.11 (d, J=6.90 Hz, 1H), 4.35 (t, J=6.0 Hz, 2H), 5.49 (s, 1H), 6.00 (d, J=2.4 Hz, 1H), 6.52 (dd, J=9.0 Hz, 2.7 Hz, 1H), 6.93 (d, J=9.0 Hz, 2H), 7.42 (d, J=8.4 Hz, 2H), 7.90 (d, J=9.0 Hz, 1H).

Step 2: Preparation of ester intermediate

A solution of 520 mg (0.85 mmol) of butyl mesylate intermediate (obtained from Step 1) and 191 mg (1.71 mmol) of DABCO in 10 mL of acetonitrile was stirred at 80° C. for 4 hours. The reaction mixture was concentrated in vacuo to yield a white foam. The foam was crushed and washed with ether. The solid was filtered off and dried in vacuo to give 540 mg (88%) of the desired title compound which was recrystallized from methylene chloride and acetone as a white solid: mp 248-251° C.; ¹ H NMR (CDCl₃) δ 0.91 (m, 6H), 1.14-1.47 (m, 14H), 1.63 (m, 1H), 1.96 (m, 4H), 2.21 (m, 1H), 2.77 (s, 3H), 2.82 (s, 3H), 3.07 (ABq, 2H), 3.26 (t, J=7.1 Hz, 6H), 3.60 (m, 8H), 4.08 (m, 3H), 5.47 (s, 1H), 5.99 (d, J=2.4 Hz, 1H), 6.51 (dd, J=8.9 Hz, 2.6 Hz, 1H), 6.91 (d, J=8.7 Hz, 2H), 7.41 (d, J=8.1 Hz, 2H), 7.89 (d, J=9.0 Hz, 1H).

Example 1409 ##STR489## (4R-cis)-1-[4-[4-[3,3-Dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4-hydroxy-1,1-dioxido-1-benzothiepin-5-yl]phenoxy]butyl]-4-aza-1-azoniabicyclo[2.2.2]octane-4-methylbenzenesulfonate (salt)

Step 1: Preparation of propyl tosylate intermediate

A solution of 5-(4'-hydroxyphenyl)-7-(dimethylamino)tetrahydrobenzothiepine-1,1-dioxide (5.0 g, 10.9 mmol, obtained from Example 1402, Step 10) in acetone (100 mL) at 25° C. under N₂ was treated with powdered K₂ CO₃ (3.8 g, 27.2 mmol, 2.5 eq.) and 1,4-butanediol di-p-tosylate (13.0 g, 32.6 mmol, 3.0 eq.), and the resulting solution was stirred at 65° C. for 21 hours. The cream-colored slurry was cooled to 25° C. and filtered through a sintered glass funnel. The filtrate was concentrated and the residue was dissolved in EtOAc (150 mL). The organic layer was washed with saturated aqueous NaHCO₃ (2×150 mL) and saturated aqueous NaCl (2'150 mL). The extract was dried (MgSO₄) and concentrated in vacuo to provide a pale orange oil. Purification by flash chromatography (4.4×35 cm silica, 20-30% EtOAc/hexane) afforded the propyl tosylate intermediate (6.0 g, 80%) as a white foam: ¹ H NMR (CDCl₃) δ 0.89 (m, 6H), 1.10-1.44 (br m, 10H), 1.61 (m, 1H), 1.84 (m, 4H), 2.19 (m, 1H), 2.43 (s, 3H), 2.80 (s, 6H), 3.03 (ABq, J=15.1 Hz, J=46.3 Hz, 2H), 3.93 (m, 2H), 4.06-4.13 (m, 4H), 5.44 (s, 1H), 5.96 (s, 1H), 6.46 (dd, J=8.9, 1.4 Hz, 1H), 6.85 (d, J=8.1 Hz, 2H), 7.33 (d, J=8.1 Hz, 2H), 7.38 (d, J=8.1 Hz, 2H), 7.78 (d, J=8.9 Hz, 2H), 7.83 (m, 1H).

Step 2: Preparation of quaternary salt

A solution of propyl tosylate intermediate (5.8 g, 8.5 mmol, obtained from Step 1) in acetonitrile (100 mL) at 25° C. under N₂ was treated with diazabicyclo[2.2.2]octane (DABCO, 1.1 g, 10.1 mmol, 1.2 eq.) and stirred at 45° C. for 6 hours. The pale yellow solution was cooled to 25° C. and concentrated in vacuo to provide an off-white solid. The residue was dissolved in a minimal amount of CH₂ Cl₂ (5 mL) and diluted with Et₂ O (100 mL) while vigorously stirring for 3 hours, during which time a white solid precipitated. The white solid was collected and recrystallized from EtOAc/hexane to give the desired title compound (5.7 g, 85%) as colorless needles: mp 223-231° C. (decomposed); ¹ H NMR (CDCl₃) δ 0.86 (m, 6H), 1.09-1.43 (br m, 12H), 1.61-1.90 (br m, 5H), 2.13 (m, 1H), 2.25 (s, 3H), 2.75 (s, 6H), 3.03 (ABq, J=15.1 Hz, J=30.0 Hz, 2H), 3.05 (br s, 6H), 3.37 (br s, 6H), 3.89 (m, 2H), 4.07 (d, J=7.5 Hz, 1H), 5.39 (s, 2H), 5.97 (d, J=1.6 Hz, 1H), 6.44 (dd, J=8.9, 2.0 Hz, 1H), 6.87 (d, J=8.3 Hz, 2H), 7.08 (d, J=8.1 Hz, 2H), 7.37 (d, J=8.3 Hz, 2H), 7.71 (d, J=8.1 Hz, 2H), 7.80 (d, J=8.9 Hz, 1H); HRMS. Calc'd for C₃₆ H₅₆ N₃ O₄ S: 626.3992. Found: 626.3994. Anal. Calc'd for C₄₃ H₆₃ N₃ O₇ S₂ : C, 64.71; H, 7.96; N, 5.27. Found: C, 64.36; H, 8.10; N, 5.32.

Example 1410 ##STR490## (4R-cis)-4-[4-[3,3-Dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4-hydroxy-1,1-dioxido-1-benzothiepin-5-yl]phenoxy]-N,N,N-triethyl-1-butanaminium

A solution of 1 g (1.64 mmol) of the butyl mesylate intermediate (obtained from Example 1408, Step 1) and 15 mL of triethylamine in 10 mL of acetonitrile was heated at 50° C. for 2 days. The solvent was evaporated and the residue was triturated with ether and ethyl acetate to afford 500 mg (43%) of product as a semi-solid. ¹ H NMR (CDCl₃) δ 0.8 (m, 6 H), 1-1.6 (m, 24 H), 2.1 (m, 1 H), 2.6 (s, 3 H), 2.7 (s, 6 H), 2.9 (d, J=15 Hz, 1 H), 3.0 (d, J=15 Hz, 1 H), 3.3 (m, 8 H), 4.0 (m, 4 H), 5.3 (s, 1 H), 5.9 (s, 1 H), 6.4 (m, 1 H), 6.8 (d, J=9 Hz, 2 H), 7.4 (d, J=9 Hz, 2 H), 7.8 (d, J=7 Hz, 1 H). MS m/e 615.

Example 1411 ##STR491## (4R-cis)-1-[4-[4-[3,3-Dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4-hydroxy-1,1-dioxido-1-benzothiepin-5-yl]phenoxy]butyl]-3-hydroxypyridinium, methanesulfonate (salt)

A solution of 1 g (1.64 mmol) of the butyl mesylate intermediate (obtained from Example 1408, Step 1) and 234 mg (2.46 mmol) of 3-hydroxy pyridine in 1 mL of dimethylformamide was heated at 70° C. for 20 hours. The solvent was evaporated and the residue was triturated with ether and ethyl acetate to afford 990 mg (86%) of product as a semi-solid: ¹ H NMR (CDCl₃) δ0.9 (m, 6 H), 1-1.5 (m, 10 H), 1.7 (m, 1 H), 1.9 (m, 2 H), 2-2.4 (m, 3 H), 2.9 (s, 6 H), 3.1 (d, J=15 Hz, 1 H), 3.2 (d, J=15 Hz, 1 H), 4.1 (m, 3 H), 4.7 (m, 2 H), 5.5 (s, 1 H), 6.1 (s, 1 H), 6.6 (m, 1 H), 6.9 (d, J=9 Hz, 2 H), 7.4 (d, J=9 Hz, 2 H), 7.7 (m, 1 H), 8.0 (m, 2 H), 8.2 (m, 1 H), 9.1 (s, 1 H). MS m/e 609.

Example 1412 ##STR492## (4R-cis)-1-[5-[4-[3,3-Dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4-hydroxy-1,1-dioxido-1-benzothiepin-5-yl]phenoxy]pentyl]quinolinium, methanesulfonate (salt)

Step 1: Preparation of pentyl mesylate intermediate

To a stirred solution of 231 mg (5.79 mmol, 60% disp.) of NaH in 22 mL of DMF was added 2.05 g (4.45 mmol) of 5-(4'-hydroxyphenyl)-7-(dimethylamino)tetrahydrobenzothiepine-1,1-dioxide (obtained from Example 1402, Step 10), and the resulting solution was stirred at ambient temperature for 1 hour. To the mixture was added 18.02 g (55.63 mmol) of 1,5-diiodopentane and the solution was stirred overnight at ambient temperature. DMF was removed by high vacuum and the residue was extracted with ethyl acetate and washed with brine. The extract was dried over MgSO₄, and the concentrated residue was purified by column chromatography to give the pentyl mesylate intermediate: ¹ H NMR (CDCl₃) δ0.90(q, 6H), 1.05-2.0 (m, 17H), 2.2 (t, 1H), 2.8 (s, 6h), 3.0 (q, 2H), 3.22 (t, 2H), 3.95 (t, 2H), 4.1 (s, 1H), 5.42 (s, 1H), 6.1 (d, 1H), 6.6 (d, 1H), 6.9 (d, 2H), 7.4 (d, 2H), 7.9 (d, 1H).

Step 2: Preparation of quaternary salt

To 1.0 g (1.53 mmol) of the pentyl mesylate intermediate (obtained from Step 1) was added 3.94 g (30.5 mmol) of quinoline and 30 mL of acetonitrile. The solution was heated at 45° C. under N₂ for 10 days. The concentrated residue was purified by reverse phase C18 column chromatography. The obtained material was exchanged to its mesylate anion by ion exchange chromatography to give the desired title compound as a solid: mp 136° C.; ¹ H NMR (CDCl₃) δ 0.95(q, 6H), 1.05-2.25 (m, 18H), 2.8 (s, 9H), 3.0 (q, 2H), 3.95 (t, 2H), 4.1 (s, 1H), 5.28 (t, 2H), 5.42 (s, 1H), 5.95 (s, 1H), 6.45 (d, 1H), 6.82 (d, 2H), 7.4 (d, 2H), 7.82 (d, 1H), 7.9 (t, 1H), 8.2 (t, 2H), 8.3 (q, 2H), 8.98 (d, 1H), 10.2 (d, 1H). HRMS. Calc'd for C₄₀ H₅₃ N₂ O₄ S: 657.3726. Found: 657.3736. Anal. Calc'd for C₄₀ H₅₃ N₂ O₄ S.CH₃ O₃ S: C, 65.40; H, 7.50; N, 3.72; S, 8.52. Found: C, 62.9; H, 7.42; N, 3.56; S, 8.41.

Example 1413 ##STR493## (4S-cis)-[5-[4-[3,3-Dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4-hydroxy-1,1-dioxido-1-benzothiepin-5-yl]phenoxy]pentyl]propanedioic acid

Step 1: Preparation of pentyl bromide intermediate

To a stirred solution of 0.63 g (15.72 mmol, 60% disp) of NaH in 85 mL of DMF was added 6.0 g (13.1 mmol) of 5-(4'-hydroxyphenyl)-7-(dimethylamino)tetrahydrobenzothiepine-1,1-dioxide (obtained from Example 1402, Step 10), and the resulting solution was stirred at ambient temperature for 1 hour. To the solution was added 37.7 g (163.75 mmol) of 1,5-dibromopentane, and the mixture was stirred overnight at ambient temperature. DMF was removed in vacuo and the residue was extracted with ethyl acetate and washed with brine. The extract was dried over MgSO₄, and the concentrated residue was purified by column chromatography to give the pentyl bromide intermediate: ¹ H NMR (CDCl₃) δ 0.90 (q, 6H), 1.05-2.0 (m, 17H), 2.2 (t, 1H), 2.8 (s, 6H), 3.0 (q, 2H), 3.4 (t, 2H), 3.95 (t, 2H), 4.1 (s, 1H), 5.42 (s, 1H), 6.0 (s, 1H), 6.5 (d, 1H), 6.9 (d, 2H), 7.4 (d, 2H), 7.9 (d, 1H).

Step 2: Preparation of dibenzyl ester intermediate

To the mixture of 59 mg (1.476 mmol, 60% disp) of NaH in 27 mL of THF and 9 mL of DMF at 0° C. was added 0.84 g (2.952 mmol) of dibenzyl malonate (Aldrich), and the resulting solution was stirred at ambient temperature for 15 min. To the solution was added 0.5987 g (0.984 mmol) of the pentyl bromide intermediate, and the mixture was stirred at 80° C. overnight. Solvent was removed in vacuo, and the residue was extracted with methylene chloride and washed with brine. The extract was dried over MgSO₄, and the concentrated residue was purified by column chromatography to give the dibenzyl ester intermediate: ¹ H NMR (CDCl₃) δ 0.90 (q, 6H), 1.05-2.0 (m, 19H), 2.2 (t, 1H), 2.8 (s, 6H), 3.0 (q, 2H), 3.4 (t, 1H), 3.9 (t, 2H), 4.1 (d, 1H), 5.18 (s, 4H), 5.42 (s, 1H), 5.95 (s, 1H), 6.5 (d, 1H), 6.9 (d, 2H), 7.2-7.4 (m, 12H), 7.85 (d, 1H).

Step 3: Preparation of diacid

A suspension of 0.539 g (0.664 mmol) of the dibenzyl ester intermediate (obtained from Step 2) and 25 mg of 10% Pd/C in 30 mL of ethanol was agitated at ambient temperature under 20 psi of hydrogen gas for 2 hours. The catalyst was filtered off, and the filtrate was concentrated to give the desired title compound as a solid: mp 118° C.; ¹ H NMR (CDCl₃) δ 0.9 (d, 6H), 1.05-2.2 (m, 20H), 2.8 (s, 6H), 3.0 (q, 2H), 3.4 (s, 1H), 3.95 (s, 2H), 4.1 (s, 1H), 5.42 (s, 1H), 5.95 (s, 1H), 6.5 (d, 1H), 6.9 (d, 2H), 7.4 (d, 2H), 7.85 (d, 1H). HRMS. Calc'd for C₃₄ H₄₉ NO₈ S: 632.3257. Found: 632.3264. Anal. Calc'd for C₃₄ H₄₉ NO₈ S: C, 64.63; H, 7.82; N, 2.22; S, 5.08. Found: C, 63.82; H, 7.89; N, 2.14; S, 4.93.

Example 1414 ##STR494## (4R-cis)-3,3-Dibutyl-5-[4-[[5-(diethylamino)pentyl]oxy]phenyl]-7-(dimethylamino)-2,3,4,5-tetrahydro-1-benzothiepin-4-ol 1,1-dioxide

Step 1: Preparation of pentyl iodide intermediate

To a solution of 5-(4'-hydroxyphenyl)-7-(dimethylamino)tetrahydrobenzothiepine-1,1-dioxide (3 g, 6.53 mmol, obtained from Example 1402, Step 10) in 100 mL of dimethylformamide was added 198 mg (7.83 mmol) of 95% sodium hydride. The mixture was stirred 15 minutes at room temperature and diiodopentane was added. After one hour at room temperature the mixture was diluted in ethyl acetate and water. The aqueous layer was extracted with ethyl acetate and the combined organic layer was washed with brine, dried over magnesium sulfate and concentrated in vacuo. The residue was chromatographed over silica gel, eluting with hexane/ethyl acetate (1/5) to afford 2.92 g (4.46 mmol) of the pentyl iodide intermediate: ¹ H NMR (CDCl₃) δ 0.9 (m, 6 H), 1-1.5 (m, 11 H), 1.6 (m, 3 H), 1.8 (m, 4 H), 2.2 (m, 1 H), 2.8 (s, 6 H), 3.0 (d, J=15 Hz, 1 H), 3.2 (d, J=15 Hz, 1 H), 3.3 (m, 2 H), 4.0 (m, 1 H), 4.1 (s, 1 H), 5.5 (s, 1 H), 6.1 (s, 1 H), 6.6 (m, 1 H), 6.9 (d, J=9 Hz, 2 H), 7.4 (d, J=9 Hz, 2 H), 7.9 (d, J=7 Hz, 1 H).

Step 2: Preparation of amine

A solution of 550 mg (0.76 mmol) of the pentyl iodide intermediate (obtained from Step 1) and 279 mg (3.81 mmol) of diethylamine in 3 mL of acetonitrile was stirred at 100° C. overnight. The mixture was concentrated in vacuo to yield a yellowish brown foam. The foam was dissolved in 10 mL of ethyl acetate and washed with 50 mL of saturated sodium carbonate solution twice. The ethyl acetate layer was dried over magnesium sulfate and concentrated to yield 390 mg (85%) of the desired title compound as a yellow foamy solid: ¹ H NMR (CDCl₃) δ 0.89 (m, 6H), 1.20-1.47 (m, 12H), 1.53-1.67 (m, 4H), 1.76-1.90 (m, 8H), 2.21 (m, 1H), 2.74-2.92 (m, 12H), 3.07 (ABq, 2H), 4.00 (t, J=6.3 Hz, 2H), 4.10 (d, J=7.8 Hz, 1H), 5.48 (s, 1H), 6.00 (d, J=2.4 Hz, 1H), 6.51 (dd, J=9.2 Hz, 2.6 Hz, 1H), 6.92 (d, J=8.7 Hz, 2H), 7.41 (d, J=8.4 Hz, 2H), 7.90 (d, J=9.0 Hz, 1H).

Example 1415 ##STR495## (4R-cis)-N-(Carboxymethyl)-N-[5-[4-[3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4-hydroxy-1,1-dioxido-1-benzothiepin-5-yl]phenoxy]pentyl]glycine

Step 1: Preparation of diester intermediate

A mixture of 8.6 g (14.1 mmol) of pentyl bromide intermediate (obtained from Example 1413, Step 1), 65 g (0.35 mol) of diethylaminodiacetate and 7.5 g (71 mmol) of anhydrous Na₂ CO₃ was stirred at 160° C. for 3 hours. The reaction mixture was diluted with water and extracted with methylene chloride. The volatiles was removed in vacuo to give 9.6 g (95%) of the diester intermediate. ¹ H NMR spectrum was consistent with the structure; MS (M+H) m/e 717.

Step 2: Preparation of diacid

The mixture of the diester intermediate (obtained from Step 1) and 2.7 g (64.3 mmol) of LiOH in THF (75 mL) and water (50 mL) was stirred at 40° C. for 18 hours. The reaction mixture was acidified with 1% HCl and extracted with dichloromethane. The residue was triturated with hexane, filtered to give 8.9 g (93%) of the desired title compound as a solid: mp 148-162° C.; ¹ H NMR (CD₃ OD) δ 0.92 (t, 6H), 1.1-1.9 (m, 31H), 2.15 (t, 1H), 2.8(s, 6H), 3.15 (ABq, 2H), 3.75(m, 1H), 4.1 (m, 6H), 5.3(s, 1H), 6.1 (s, 1H), 6.6 (d, 1H), 7.0(d, 2H), 7.4 (d, 2H), 7.8 (d, 1H); MS (M+H) m/e 661. Anal. Calc'd for [C₃₅ H₅₂ N₂ O₈ S+1.5H₂ O]: C,61.11; H,8.06; N,4.07; S,4.66. Found: C,61.00; H,7.72; N,3.89; S,4.47.

Example 1416 ##STR496## (4R-cis)-5-[4-[[5-[bis[2-(Diethylamino)ethyl]amino]pentyl]oxy]phenyl]-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-1-benzothiepin-4-ol 1,1-dioxide

A solution of 1 g of pentyl iodide intermediate (1.53 mmol, obtained from Example 1414, Step 1) in N,N,N',N'-tetraethyl diethylenetriamine was heated to 80° C. for 4 hours. The mixture was dissolved in ethyl acetate and saturated NaHCO₃. The organic layer was washed with brine, dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by reverse phase chromatography. The fractions containing the product were concentrated in vacuo, dissolved in ethyl acetate and washed with saturated NaHCO₃. The residue was dried and concentrated in vacuo to afford 840 mg (74%) of the desired title compound as a thick oil. ¹ H NMR (CDCl₃) δ 0.8 (m, 6 H), 1-1.6 (m, 28 H), 1.8 (m, 2 H), 2.1 (m, 1 H), 2.5 (m, 18 H), 2.7 (s, 6 H), 2.9 (d, J=15 Hz, 1 H), 3.1 (d, J=15 Hz, 1 H), 3.9 (m, 2 H), 4.0 (m, 1 H), 4.1 (s, 1 H), 5.4 (s, 1 H), 6.0 (s, 1 H), 6.4 (m, 1 H), 6.9 (d, J=9 Hz, 2 H), 7.4 (d, J=9 Hz, 2 H), 7.8 (d, J=7 Hz, 1 H). MS (M+H) m/e 743.

Example 1417 ##STR497## (4R-cis)-3,3-Dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-5-[4-[[5-[[2-(1H-imidazol-4-yl)ethyl]amino]pentyl]oxy]phenyl]-1-benzothiepin-4-ol 1,1-dioxide

A solution of 1 g of pentyl iodide intermediate (1.53 mmol, obtained from Example 1414, Step 1) and 3.4 g (30.6 mmol) of histamine was heated to 50° C. for 17 hours. The mixture was dissolved in ethyl acetate and saturated NaHCO₃. The organic layer was washed with brine, dried over magnesium sulfate, and concentrated in vacuo. The residue was triturated with ether to afford 588 mg (60%) of the desired title compound as a semi-solid: ¹ H NMR (CDCl₃) δ 0.9 (m, 6 H), 1-1.7 (m, 14 H), 1.9 (m, 3 H), 2.0 (m, 2 H), 2.2 (m, 1 H), 2.8 (s, 6 H), 3.0 (m, 3 H), 3.2 (m, 2 H), 4.0 (m, 2 H), 4.1 (m, 3 H), 5.5 (s, 1 H), 6.0 (s, 1 H), 6.5 (m, 1 H), 6.8 (s, 1 H), 6.9 (d, J=9 Hz, 2 H), 7.4 (m, 3 H), 7.9 (d, J=8 Hz, 1 H). MS (M+H) m/e 639.

Example 1418 ##STR498## (4R-cis)-N-[5-[4-[3,3-Dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4-hydroxy-1,1-dioxido-1-benzothiepin-5-yl]phenoxy]pentyl]-N'-ethyl-N,N,N',N'-tetramethyl-1,2-ethanediaminium dichloride

Step 1: Preparation of pentyl bromide intermediate

A mixture of 5-(4'-hydroxyphenyl)-7-(dimethylamino)tetrahydrobenzothiepine-1,1-dioxide (1.680 g, 3.66 mmol, obtained from Example 1402, Step 10) and sodium hydride (0.250 g, 6.25 mmol) in 30 mL of DMF was stirred in a dry 100 mL round-bottom flask under N₂. To this solution was added 1,5-dibromopentane (6.0 mL/44.0 mmol), and the resulting mixture was stirred for 18 hours. The reaction was diluted with brine (100 mL) and H₂ O (20 mL), and the mixture was extracted with EtOAc (3×50 mL). Organic layers were combined, dried (MgSO₄), filtered and concentrated in vacuo. Purification by filtration through silica gel eluting with 20% EtOAc/hexane and evaporation in vacuo gave pentyl bromide intermediate as a white foamy solid (1.783 g, 80%): ¹ H NMR (CDCl₃) δ 0.84-0.95 (m, 6H), 1.02-1.56 (m, 10H), 1.58-1.70 (m, 3H), 1.78-2.03 (m, 4H), 2.15-2.24 (m, 1H), 2.77 (s, 1H), 2.80 (s, 6H), 3.05 (ABq, 2H), 3.42 (t, 2H), 3.98 (t, 2H), 4.10 (s, 1H), 5.47 (s, 1H), 5.99 (d, 1H), 6.50 (dd, 1H), 6.91 (d, 2H), 7.40 (d, 2H), 7.88 (d, 1H).

Step 2: Preparation of mono-quaternary salt

The mixture of pentyl bromide intermediate (0.853 g, 1.40 mmol, obtained from Step 1), N,N,N',N'-tetramethylethylenediamine (1.0 mL/6.62 mmol) in 30 mL of acetonitrile was stirred at 40° C. for 12 hours, and the reaction mixture was concentrated in vacuo to give an off-white foamy solid (1.052 g). The crude product was dissolved in acetonitrile (1.5 mL) and triturated with ethyl ether. The solvent was decanted to yield a sticky solid. This trituration method was repeated twice, and the resulting sticky solid was concentrated in vacuo to give the mono-quaternary salt as an off-white foamy solid (0.951 g, 94%): ¹ H NMR (CDCl₃) δ 0.81 (t, 6H), 0.96-1.64 (m, 13H), 1.62-1.85 (m, 4H), 2.03-2.18 (m, 1H), 2.20 (s, 6H), 2.67 (t, 2H), 2.74 (s, 6H), 2.98 (ABq, 2H), 3.30-3.42 (m, 1H), 3.38 (s, 6H), 3.60-3.75 (m, 4H), 3.90 (t, 2H), 4.01 (s, 1H), 5.37 (s, 1H), 5.92 (s, 1H), 6.41 (dd, 1H), 6.81 (d, 2H), 7.32 (d, 2H), 7.77 (d, 1H).

Step 3: Preparation of di-quaternary salt

The mono-quaternary salt (0.933 g, 1.29 mmol, obtained from Step 2), iodoethane (0.300 mL/3.75 mmol), and acetonitrile (30.0 mL) were combined in a 4 oz. Fischer Porter bottle. The reaction vessel was purged with N₂, sealed, equipped with magnetic stirrer, and heated to 50° C. After 24 hours, the reaction mixture was cooled to ambient temperature and concentrated in vacuo to give a yellow foamy solid (1.166 g). The solid was dissolved in methylene chloride/acetonitrile and precipitated with ethyl ether. After cooling to 0° C. overnight, the resulting solid was filtered, washed with ethyl ether and concentrated in vacuo to yield the di-quaternary salt as an off-white solid (1.046 g, 92%): ¹ H NMR (CD₃ OD) δ 0.59 (t, 6H), 0.70-1.10 (m, 9H), 1.16 (t, 3H), 1.22-1.80 (m, 9H), 2.42 (s, 6H), 2.78 (d, 2H), 2.98 (s, 6H), 3.02 (s, 6H), 3.22-3.37 (m, 4H), 3.63-3.78 (m, 4H), 3.80 (s, 4H), 4.93 (s, 1H), 5.71 (s, 1H), 6.22 (dd, 1H), 6.61 (d, 2H), 7.02 (d, 2H), 7.40 (d, 1H).

Step 4: Preparation of quaternary di-chloride salt

The iodobromosalt (obtained from Step 3) was converted to its corresponding dichloride salt using Biorad AG 2×8 resin and eluting with 70% H₂ O/acetonitrile to give the desired title compound as a white foamy solid (0.746 g, 84%): mp 193.0-197.0° C.; ¹ H NMR (CD₃ OD) δ 0.59 (t, J=6.0 Hz, 6H), 0.70-1.12 (m, 9H), 1.16 (t, J=6.6 Hz, 3H), 1.24-1.90 (m, 9H), 2.50 (s, 6H), 2.78 (s, 2H), 3.08 (s, 6H), 3.11 (s, 6H), 3.24-3.50 (m, 4H), 3.68 (s, 2H), 3.81 (s, 2H), 4.16 (s, 4H), 5.02 (s, 1H), 5.72 (s, 1H), 6.19 (d, J=8.4 Hz, 1H), 6.61 (d, J=8.1 Hz, 2H), 7.10 (d, J=7.8 Hz, 2H), 7.46 (d, J=8.7 Hz, 1H). HRMS. Calc'd for C₃₉ H₆₇ N₃ O₄ SCl: 708.4541. Found: 708.4598.

Example 1419 ##STR499## [4R-[4a,5a(4R*,5R*)]]-N,N'-bis[5-[4-[3,3-Dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4-hydroxy-1,1-dioxido-1-benzothiepin-5-yl]phenoxy]pentyl]-N,N,N'N'-tetramethyl-1,6-hexanediaminium dichloride

The pentyl bromide intermediate (1.002 g, 1.64 mmol, obtained from Example 1418, Step 1) and N,N,N',N'-tetramethyl-1,6-hexanediamine (0.100 g, 0.580 mmol) in 5 mL of acetonitrile were placed in a 4 oz. Fischer Porter bottle. The reaction vessel was purged with N₂, sealed, equipped with magnetic stirrer and heated to 50° C. After 15 hours, the reaction mixture was cooled to ambient temperature and concentrated in vacuo to give an off-white foamy solid (1.141 g). The solid was dissolved in acetonitrile and precipitated with ethyl ether. After cooling to 0° C., the solvent was decanted to yield a sticky off-white solid. This trituration method was repeated, and the resulting sticky solid was concentrated in vacuo to give the desired dibromide salt as an off-white foamy solid (0.843 g, quantitative): ¹ H NMR (CDCl₃) δ 0.85 (m, 12H), 1.01-1.70 (m, 30H), 1.76-2.08 (m, 12H), 2.18 (t, J=12.3 Hz, 2H), 2.79 (s, 12H), 3.03 (ABq, 4H), 3.35 (s, 12H), 3.52 (br s, 6H), 3.72 (br s, 4H), 3.97 (br s, 4H), 4.08 (br s, 2H), 5.42 (s, 2H), 6.00 (s, 2H), 6.51 (d, J=9.0 Hz, 2H), 6.86 (d, J=7.8 Hz, 4H), 7.38 (d, J=7.8 Hz, 4H), 7.83 (d, J=8.7 Hz, 2H). The dibromide salt was converted to its corresponding dichloride salt using Biorad AG 2×8 resin and eluting with 70% H₂ O/CH₃ CN to give the desired title compound as a white foamy solid (0.676 g, 86%): mp 178.0-182.0° C.; ¹ H NMR (CDCl₃) δ 0.80-0.90 (m, 12H), 1.01-1.70 (m, 30H), 1.75-2.06 (m, 12H), 2.16 (t, J=12.9 Hz, 2H), 2.79 (s, 12H), 3.03 (ABq, 4H), 3.33 (s, 12H), 3.49 (br s, 6H), 3.70 (br s, 4H), 3.96 (t, J=5.4 Hz, 4H), 4.08 (s, 2H), 5.42 (s, 2H), 5.986 (s, 1H), 5.993 (s, 1H), 6.49 (d, J=9.0 Hz, 1H), 6.50 (d, J=9.0 Hz, 1H), 6.87 (d, J=8.4 Hz, 4H), 7.38 (d, J=8.1 Hz, 4H), 7.84 (d, J=8.7 Hz, 2 H). HRMS. Calc'd for C₃₆ H₅₈ N₂ O₄ S: 614.4118. Found: 614.4148.

Example 1420 ##STR500## (4R-cis)-3,3-Dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-5-[4-[[5-(1H-tetrazol-5-yl)pentyl]oxy]phenyl]-1-benzothiepin-4-ol 1,1-dioxide

Step 1: Preparation of pentyl bromide intermediate

To a stirred suspension of 1.01 g (25.4 mmol, 60% oil dispersion) of sodium hydride in 150 mL of DMF was added 9.0 g (19.5 mmol) of 5-(4'-hydroxyphenyl)-7-(dimethylamino)tetrahydrobenzothiepine-1,1-dioxide (obtained from Example 1402, Step 10) in portions. After 30 minutes the reaction was cooled in a water bath (15° C.) and 4.48 g (195 mmol) of 1,5-dibromopropane was added. The reaction was stirred at ambient temperature for 1.5 hours and quenched with 50 mL of saturated NH₄ Cl. The reaction was diluted with ethyl acetate, washed with water, brine, dried over MgSO₄, filtered and concentrated in vacuo. Purification by silica gel chromatography (Waters-Prep 500) using 25% ethyl acetate/hexanes afforded 10.17 g (85%) of the pentyl bromide intermediate as a colorless foam: mp 65-70° C.; ¹ H NMR (CDCl₃) δ 0.84-0.98 (M, 6H), 1.04-1.52 (m, 10H), 1.58-1.65 (m, 3H), 1.82 (p, J=6.8 Hz, 2H), 1.94 (p, J=7.0 Hz, 2H), 2.12-2.26 (m, 1H), 2.82 (s, 6H), 3.06 (AB_(q), J_(AB) =15.2, 45.3 Hz, 2H), 3.44 (t, J=6.7 Hz, 2H), 3.99 (t, J=6.3 Hz, 2H), 4.10 (s, 1H), 5.47 (s, 1H), 6.15 (d, J=2.7 Hz, 1H), 6.68 (dd, J=2.5, 8.4 Hz, 1H), 6.91 (d, J=8.4 Hz, 2H), 7.39 (d, J=8.4 Hz, 2H), 7.93 (d, J=8.7 Hz, 1H).

Step 2: Preparation of pentyl nitrile intermediate

To a stirred solution of 378 mg (0.621 mmol) of the pentyl bromide intermediate (obtained from Step 1) in 1 mL of DMSO was added 37 mg (0.745 mmol) of sodium cyanide. The reaction was stirred at ambient temperature for 16 hours. The reaction was concentrated under a nitrogen stream and the residue partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over MgSO₄, filtered, and concentrated in vacuo to afford 278 mg (93% RPHPLC purity, ca. 75%) of the pentyl nitrile intermediate as a colorless foam: ¹ H NMR (CDCl₃) δ0.86-0.96 (m, 6H), 1.02-1.21(m, 1H), 1.21-1.52 (m, 19H), 1.58-1.92 (m, 7H), 2.16-2.28 (m, 1H), 2.41 (t, J=6.9 Hz, 2H), 2.83 (s, 6H), 3.08 (AB_(q), 15.0, 47.5 Hz, 2H), 4.01 (t, J=6.2 Hz, 2H), 4.1 (s, 1H), 5.49 (s, 1H), 6.07 (d, J=2.1 Hz, 1H), 6.59 (dd, J=2.4, 8.7 Hz, 1H), 6.92 (d, J=8.1 Hz, 2H), 7.42 (d, J=8.4 Hz, 2H), 7.92 (d, J=8.7 Hz, 1H). MS (ES, M+H) m/e 555.

Step 3: Preparation of tetrazole

A solution of 275 mg (0.5 mmol) of the nitrile intermediate (obtained from Step 2) and 666 mg (3.23 mmol) of azidotrimethyltin in 5 mL of toluene was stirred with heating at 80° C. for 60 hours. The reaction was concentrated under a nitrogen stream. Purification by reversed phase chromatography (Waters-Delta prep) using 60% water/acetonitrile afforded 226 mg of the desired title compound (75%) as a colorless foam: mp 80-85° C.; ¹ H NMR (CDCl₃) δ 0.83-0.95 (m, 6H), 1.30-1.52 (m, 10H), 1.52-1.73 (m, 3H), 1.79-1.99 (m, 4H), 2.14-2.26 (m, 1H), 2.91 (s, 6H), 3.02-3.22 (m, 4H), 3.92-4.06 (m, 2H), 4.16 (s, 1H), 5.47 (s, 1H), 6.28 (d, J=2.4 Hz, 1H), 6.74 (dd, J=2.7, 8.8 Hz, 1H), 6.89 (d, J=8.7 Hz, 2H), 7.37 (d, J=8.1 Hz, 2H), 7.98 (d, J=8.7 Hz, 1H). HRMS Calc'd for C₃₂ H₄₈ N₅ O₄ S: 598.3427. Found: 598.3443.

Example 1421 ##STR501## (4R-cis)-4-[[5-[4-[3,3-Dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4-hydroxy-1,1-dioxido-1-1benzothiepin-5-yl]phenoxy]pentyl]oxy]-2,6-pyridinecarboxylic acid

Step 1: Preparation of pentyl bromide intermediate

To a solution of 0.63 g (15.72 mmol, 60% disp) of NaH in 85 mL of DMF was add 6.0 g (13.1 mmol) of 5-(4'-hydroxyphenyl)-7-(dimethylamino)tetrahydrobenzothiepine-1,1-dioxide (obtained from Example 1402, Step 10), and the resulting solution was stirred at ambient temperature for 1 hour. To the solution was added 37.7 g (163.75 mmol) of 1,5-dibromopentane, and stirred overnight at ambient temperature. DMF was removed in vacuo and the residue was extracted with ethyl acetate and washed with brine. The extract was dried over MgSO₄, and the concentrated residue was purified by column chromatography to give the pentyl bromide intermediate: ¹ H NMR (CDCl₃) δ 0.90 (q, 6H), 1.05-2.0 (m, 17H), 2.2 (t, 1H), 2.8 (s, 6H), 3.0 (q, 2H), 3.4 (t, 2H), 3.95 (t, 2H), 4.1 (s, 1H), 5.42 (s, 1H), 6.0 (s, 1H), 6.5 (d, 1H), 6.9 (d, 2H), 7.4 (d, 2H), 7.9 (d, 1H).

Step 2: Esterification of chelidamic acid

A solution of 10 g (54.6 mmol) of chelidamic acid, 23.0 g (120.12 mmol) of 1-(3-dimethyl amino propyl)-3 ethyl carbodiimide hydrochloride, 1.33 g (10.8 mmol) of 4-dimethyl amino pyridine, and 12.4 mL (120.12 mmol) of benzyl alcohol in 100 mL of DMF was stirred at ambient temperature overnight under N₂. DMF was removed in vacuo and the residue was extracted with methylene chloride, washed with 5% NaHCO₃, 5% acetic acid, H₂ O, and brine. The extract was dried over MgSO₄, and the concentrated residue was purified by column chromatography to give dibenzyl chelidamic ester: ¹ H NMR (CDCl₃) δ 5.4 (s, 4H), 7.4 (m, 12H).

Step 3: Preparation of pyridinyl benzyl ester intermediate

A solution of 79 mg (1.972 mmol, 60% disp) of NaH and 0.716 g (1.972 mmol) of dibenzyl chelidamic ester (obtained from Step 2) in 17.5 mL of DMF was stirred at ambient temperature for 1 hour. To the solution was added 1.0 g (1.643 mmol) of the pentyl bromide intermediate and the mixture was stirred under N₂ overnight at 40° C. DMF was removed in vacuo, and the residue was extracted with ethyl acetate and washed with brine. The extract was dried over MgSO₄, and the concentrated residue was purified by column chromatography to give the pyridinyl dibenzyl ester intermediate: ¹ H NMR (CDCl₃) δ 0.90 (q, 6H), 1.05-2.0 (m, 19H), 2.2 (t, 1H), 2.8 (s, 6H), 3.0 (q, 2H), 4.0 (t, 2H), 4.1 (s, 1H), 5.4 (s, 4H), 5.42 (s, 1H), 6.0 (s, 1H), 6.5 (d, 1H), 6.9 (d, 2H), 7.3-7.5 (m, 12H), 7.78 (s, 2H), 7.9 (d, 1H).

Step 4: Preparation of pyridinyl diacid

A suspension of 0.8813 g (0.99 mmole) of dibenzyl ester (obtained from Step 3) and 40 mg of 10% Pd/C in 35 mL of ethanol and 5 mL of THF was agitated at ambient temperature under 20 psi of hydrogen gas for 2 hours. The catalyst was filtered off, and the filtrate was concentrated to give the desired title compound as a solid: mp 143° C.; 1H NMR (THF-d8) 0.95 (q, 6H), 1.05-1.65 (m, 15H), 1.9 (m, 4H), 2.22 (t, 1H), 2.8 (s, 6H), 3.0 (t, 2H), 4.1 (s, 3H), 4.3 (s, 2H), 5.4 (s, 1H), 6.05 (s, 1H), 6.5 (d, 1H), 6.9 (d, 2H), 7.4 (d, 2H), 7.78 (d, 1H), 7.82 (s, 2H). HRMS. Calc'd for C₃₈ H₅₀ N₂ O₉ S: 711.3315. Found: 711.3322. Anal. Calc'd for C₃₈ H₅₀ N₂ O₉ S: C, 64.20; H, 7.09; N, 3.94; S, 4.51. Found: C, 62.34; H, 6.97; N, 4.01; S, 4.48.

Example 1422 ##STR502## (4R-cis)-[5-[4-[3,3-Dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4-hydroxy-1,1-dioxido-1-benzothiepin-5-yl]phenoxy]pentyl]guanidine

Step 1: Preparation of pentyl azide intermediate

To a stirred solution of 200 mg (0.328 mmol) of the pentyl bromide intermediate (obtained from Example 1420, Step 1) in 0.75 mL of DMSO was added 32 mg (0.493 mmol) of sodium azide and a catalytic amount of sodium iodide. The reaction was stirred at ambient temperature for 64 hours. The reaction was concentrated under a nitrogen stream and the residue partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over MgSO₄, filtered, and concentrated in vacuo to afford 155 mg (92% RPHPLC purity, about 76% yield) of the pentyl azide intermediate as a colorless foam. Sample was used without further purification: mp 45-50° C.; ¹ H NMR (CDCl₃) δ 0.83-0.93 (m, 6H), 1.03-1.48 (m, 10H), 1.54-1.74 (m, 5H), 1.78-1.86 (m, 1H), 2.14-2.26 (m, 1H), 2.81 (s, 6H), 3.06 (AB_(q), J_(AB) =15.0, 48.0 Hz, 2H), 3.31 (t, J=6.3 Hz, 2H), 3.98 (t, J=6.3 Hz, 2H), 4.09 (s, 1H), 5.47 (s, 1H), 6.10 (d, J=1.8 Hz, 1H), 6.63 (dd, J=2.7, 9.0 Hz, 1H), 6.91 (d, J=9.0 Hz, 2H), 7.39 (d, J=8.4 Hz, 2H), 7.91 (d, J=8.7 Hz, 1H). MS (FAB, M+H) m/e 571.

Step 2: Preparation of pentyl amine intermediate

To a solution of 0.67 g (1.17 mmol) of the azide intermediate (obtained from Step 1) in 75 mL of ethanol was added 0.10 g of 10% palladium on carbon and the mixture shaken under 49 psi of hydrogen at ambient temperature for 3.5 hours. The reaction was filtered through celite and concentrated in vacuo to give 0.62 g (86% RPHPLC purity, ca. 84%) of pentyl amine intermediate as an off-white foam. The sample was used without further purification: mp 70-85° C.; ¹ H NMR (CDCl₃) δ 0.86-0.96 (m, 6H), 1.06-1.75 (m, 15H), 1.79-1.93 (m, 4H), 2.15-2.28 (m, 1H), 2.82 (s, 6H), 2.96-3.20 (m, 4H), 3.99 (t, J=6.0 Hz, 2H), 4.04-4.14 (m, 1H), 5.49 (s, 1H), 6.00 (d, J=1.5 Hz, 1H), 6.51 (d, J=9.0 Hz, 1H), 6.91 (d, J=8.4 Hz, 2H), 7.41 (d, J=8.1 Hz, 2H), 7.90 (d, J=8.7 Hz, 1H). MS (ES, M+H) m/e 545.

Step 3: Preparation of guanidine

To a stirred solution of 258 mg (0.474 mmol) of pentyl amino intermediate (obtained from Step 2) and 81 mg (0.551 mmol) of 1H-pyrazole-1-carboxamidine hydrochloride in 1.5 mL of DMF was added 71 mg (0.551 mmol) of diisopropylethylamine. The reaction was stirred at ambient temperature for 16 hours. Purification by reversed phase chromatography (Waters-Delta prep) using 60% water/acetonitrile afforded 120 mg (43%) of the desired title compound as colorless foamy solid: mp 67.0-72.5° C.; 1H NMR (CDCl₃) δ 0.89-0.93 (m, 6H), 1.05-1.17 (m, 1H), 1.26-1.90 (m, 16H), 2.07-2.24 (m, 1H), 2.81 (s, 6H), 2.99-3.19 (m, 4H), 3.98 (br s, 2H), 4.12 (s, 1H), 5.46 (s, 1H), 6.01 (d, J=2.1 Hz, 1H), 6.51 (dd, J=2.1, 8.0 Hz, 1H), 6.92 (d, J=8.1 Hz, 2H), 7.41 (d, J=7.8 Hz, 2H), 7.89 (d, J=8.7 Hz, 1H). HRMS. Calc'd for C₃₂ H₅₀ N₄ O₄ S:586.3552. Found(M+H): 587.3620.

Example 1423 ##STR503## (4R-cis)-N-[5-[4-[3,3-Dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4-hydroxy-1,1-dioxido-1-benzothiepin-5-yl]phenoxy]pentyl]glycine

Step 1: Preparation of pentyl azide intermediate

To a solution of pentyl bromide intermediate (400 mg, 0.657 mmol, obtained from Example 1420, Step 1) in dimethyl sulfoxide (20 mL) was added sodium azide (47 mg, 0.723 mmol, 1.1 eq), and the resulting clear solution was stirred at 23° C. for 16 h. The reaction solution was diluted with 100 mL ethyl acetate, then washed with water (2×100 mL) and brine (1×100 mL). The organic layer was dried (MgSO₄) and concentrated in vacuo to give 390 mg (quantitative) of pentyl azide intermediate as a yellow oil: ¹ H NMR (CDCl₃) δ 0.82-0.90 (m, 7H), 1.05-1.56 (m, 12H), 1.59-1.71 (m, 3H), 1.78-2.01 (m, 4H), 2.20 (t, J=8.3 Hz, 1H), 2.82 (s, 6H), 3.08 (q, 2H), 3.44 (t, J=7.7 Hz, 2H), 3.99 (t, J=7.7 Hz, 2H), 4.91 (br s, 1H), 5.47 (s, 1H), 6.13 (d, J=7.58 Hz, 1H), 6.68 (d, J=7.7 Hz, 1H), 7.14 (ABq, 4H), 7.91 (d, J=7.8 Hz, 1H).

Step 2: Preparation of amino ester intermediate

A suspension of pentyl azide intermediate (390 mg, 0.684 mmol, obtained from Step 1) and 100 mg of palladium on carbon in ethanol (15 mL) was agitated under an atmosphere of hydrogen gas (48 psi) for 4.5 hours. The ethanolic suspension was filtered through celite and concentrated in vacuo to give a yellow oil. The oil was immediately diluted with acetonitrile (15 mL), followed by the addition of triethylamine (0.156 g, 1.54 mmol, 2.25 eq) and bromo acetic acid benzyl ester (0.212 g, 0.925 mmol, 1.35 eq). The reaction was stirred at 23° C. for 48 hours. The reaction was concentrated in vacuo, and the residue was dissolved in ethyl acetate (20 mL) and washed with water (2×20 mL) and brine (1×20 mL). The organic layer was dried (MgSO₄) and dried in vacuo to give 420 mg (89%) of the amino ester intermediate as a yellow oil: ¹ H NMR (CDCl₃) δ 0.82-0.90 (m, 6H), 1.05-1.56 (m, 14H), 1.58-1.71 (m, 3H), 1.78-2.01 (m, 4H), 2.20 (t, J=8.3 Hz, 1H), 2.75 (d, J=7.83 Hz, 1H), 2.795 (s, 6H), 3.08 (q, 2H), 3.68-3.85 (m, 2H), 3.87-4.04 (m, 2H), 4.09 (s, 1H), 5.147 (s, 1H), 5.46 (s, 1H), 5.98 (d, J=7.58, 1H), 6.50 (dd, 1H), 6.85-6.87 (m, 2H), 7.28-7.45 (m, 5H), 7.89 (d, J=8.0 Hz, 1H). MS (ES) m/e 693.

Step 3: Preparation of acid

A suspension of benzyl ester intermediate (0.420 g, 0.61 mmol, obtained from Step 2) and 100 mg of palladium on carbon in ethanol (15 mL) was agitated under an atmosphere of hydrogen gas (48 psi) for 16 h. The suspension was filtered through celite, and concentrated in vacuo to give 0.330 g of a yellow semi-solid. The material was triturated with diethyl ether and the remaining semi-solid was dried in vacuo to give 0.19 g (52%) of the desired title compound as a yellow semi solid: ¹ H NMR (CDCl₃) δ 0.86 (br s, 7H), 1.0-1.72 (m, 18H), 1.79 (br s, 2H), 1.98 (s, 2H), 2.09-2.24 (m, 2H), 2.78 (s, 6H), 2.99 (q, 2H), 3.96 (bs, 2H), 4.08 (s, 1H), 5.46 (s, 1H), 5.97 (s, 1H), 6.40-6.49 (m, 1H), 7.14 (ABq, 4H), 7.85 (t, J=7.93 Hz, 1H). MS (ES) m/e 603.

Example 1424 ##STR504## (4R-cis)-4-[[4-[3,3-Dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4-hydroxy-1,1-dioxido-1-benzothiepin-5-yl]phenoxy]methyl]benzoic acid

Step 1: Preparation of benzoate intermediate

To a solution of 0.53 g (1.15 mmol) of 5-(4'-hydroxyphenyl)-7-(dimethylamino)tetrahydrobenzothiepine-1,1-dioxide (obtained from Example 1402, Step 10) in 10 mL dimethylformamide was added 35 mg (1.39 mmol) of 95% sodium hydride and stirred for 10 minutes. To the reaction mixture was added 525 mg (2.29 mmol) methyl 4-(bromomethyl)benzoate and stirred for 16 hours. Water was added to the reaction mixture, extracted with ethyl acetate, washed with brine, dried over magnesium sulfate, filtered and the solvent evaporated to afford 0.51 g (73%) of the benzoate intermediate: ¹ H NMR (CDCl₃) δ 0.86-0.96 (m, 6H), 1.14-1.47 (m, 10H), 1.60-1.64 (m, 1H), 2.20-2.23 (m, 1H), 2.80 (s, 6H), 2.99 (d, J=15.1 Hz, 1H), 3.15 (t, J=15.1 Hz, 1H), 3.92 (s, 3H), 4.09-4.15 (m, 1H), 5.17 (s, 2H), 5.49 (s, 1H), 5.94 (d, J=2.2 Hz, 1H), 6.50 (dd, J=8.9, 2.6 Hz, 1H), 7.00 (d, J=8.7 Hz, 2H), 7.43 (d, J=8.5 Hz, 2H), 7.53 (d, J=8.5 Hz, 2H), 7.93 (d, J=8.9 Hz, 1H), 8.06 (d, J=8.5 Hz, 2H).

Step 2: Preparation of acid

A solution of 0.51 g (0.84 mmol) of the benzoate intermediate (obtained from Step 1) and 325 mg (2.53 mmol) of KOSi(CH₃)₃ (Aldrich) in 16 mL THF was stirred for 3.5 hours. The THF was evaporated, water added, extracted with ethyl acetate, dried over magnesium sulfate, filtered and the solvent evaporated to afford 0.30 g (60%) of the desired title compound as a white solid: mp 156-159° C.; ¹ H NMR (CDCl₃) δ 0.89-0.94 (m, 6H), 1.24-1.43 (m, 10H), 1.62-1.66 (m, 1H), 2.20-2.24 (m, 1H), 2.84 (s, 6H), 3.02 (d, J=15.1 Hz, 1H), 3.17 (d, J=15.1 Hz, 1H), 4.14 (s, 1H), 5.20 (s, 2H), 5.50 (s, 1H), 6.16 (s, 1H), 6.71 (d, J=9.1 Hz, 2H), 7.03 (d, J=8.3 Hz, 2H), 7.44 (d, J=8.1 Hz, 2H), 7.57 (d, J=8.3 Hz, 2H), 7.95 (d, J=8.9 Hz, 1H), 8.13 (d, J=8.1 Hz, 2H). HRMS. Calc'd for C₃₄ H₄₄ NO₆ S: 594.2889. Found: 594.2913.

Example 1425 ##STR505## (4R-cis)-1-[[4-[[4-[3,3-Dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4-hydroxy-1,1-dioxido-1-benzothiepin-5-yl]phenoxy]methyl]phenyl]methyl]-pyridinium chloride

Step 1: Preparation of chlorobenzyl intermediate

A solution of 5-(4'-hydroxyphenyl)-7-(dimethylamino)tetrahydrobenzothiepine-1,1-dioxide (5.0 g, 10.9 mmol, obtained from Example 1402, Step 10) in acetone (100 mL) at 25° C. under N₂ was treated with powdered K₂ CO₃ (2.3 g, 16.3 mmol, 1.5 eq.) and α,α'-dichloro-p-xylene (6.7 g, 38.1 mmol, 3.5 eq.) and the resulting solution was stirred at 65° C. for 48 hours. The reaction mixture was cooled to 25° C. and concentrated to 1/5 of original volume. The residue was dissolved in EtOAc (150 mL) and washed with water (2×150 mL). The aqueous layer was extracted with EtOAc (2×150 mL) and the combined organic extracts were washed with saturated aqueous NaCl (2×150 mL. The combined extracts were dried (MgSO₄) and concentrated in vacuo to provide a yellow oil. Purification by flash chromatography (5.4×45 cm silica, 25-40% EtOAc/hexane) afforded the chlorobenzyl intermediate (4.7 g, 72%) as a white foam: ¹ H NMR (CDCl₃) δ 0.89-0.94 (m, 6H), 1.12-1.48 (br m, 10H), 1.63 (m, 1H), 2.22 (m, 1H), 2.81 (s, 6H), 3.05 (ABq, J=15.1 Hz, J=50.0 Hz, 2H), 4.11 (d, J=8.1 Hz, 1H), 4.60 (s, 2H), 5.11 (s, 2H), 5.48 (s, 1H), 5.96 (d, J=2.4 Hz, 1H), 6.48 (dd, J=8.9, 2.6 Hz, 1H), 7.00 (d, J=8.9 Hz, 2H), 7.36-7.47 (m, 5H), 7.85 (d, J=8.9 Hz, 1H).

Step 2: Preparation of quaternary salt

A solution of the chlorobenzyl intermediate (1.0 g, 1.7 mmol, obtained from Step 1) in acetonitrile (5 mL) at 25° C. under N₂ was treated with pyridine (5 mL) and stirred at 35° C. for 36 hours. The pale amber solution was cooled to 25° C. and concentrated in vacuo to give the desired title compound (1.08 g, 96%) as a yellow solid: mp 154-156° C.; ¹ H NMR (CDCl₃) δ 0.83 (m, 6H), 1.06-1.44 (br m, 10H), 1.60 (m, 1H), 2.13 (m, 1H), 2.71 (s, 6H), 3.02 (ABq, J=15.1 Hz, J=28.4 Hz, 2H), 4.09 (s, 1H), 5.00 (s, 2H), 5.38 (s, 1H), 5.91 (d, J=2.4 Hz, 1H), 6.26 (s, 2H), 6.41 (dd, J=8.9, 2.4 Hz, 1H), 6.91 (d, J=8.7 Hz, 2H), 7.26 (m, 1H), 7.40 (d, J=7.7 Hz, 4H), 7.73 (d, J=7.9 Hz, 2H), 7.78 (d, J=8.9 Hz, 2H), 7.93 (t, J=6.8 Hz, 1H), 8.34 (t, J=7.7 Hz, 1H), 8.58 (br s, 1H), 9.69 (d, J=5.8 Hz, 2H); HRMS. Calc'd for C₃₉ H₄₉ N₂ O₄ S: 641.3413. Found: 641.3425.

Example 1426 ##STR506## (4R-cis)-1-[[4-[[4-[3,3-Dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4-hydroxy-1,1-dioxido-1-benzothiepin-5-yl]phenoxy]methyl]phenyl]methyl]-4-aza-1-azoniabicyclo[2.2.2]octane chloride

Under N₂, a solution of 8.7 g (14.5 mmol) of the chlorobenzyl intermediate (obtained from a procedure similar to the one outlined in Example 1425, Step 1) in 60 mL of acetonitrile was added dropwise over a 30 min period to a solution of 2.9 g (26.2 mmol) of diazabicyclo[2.2.2]octane (DABCO) in 40 mL of acetonitrile at 35° C.; during the addition, a colorless precipitate was formed. The slurry was stirred at 35° C. for an additional 2 h. The product was collected and washed with 1 L of acetonitrile to give 9.6 g (93%) the title compound as a colorless crystalline solid: mp 223-230° C. (decomposed); ¹ H NMR (CDCl₃) δ 0.89 (m, 6H), 1.27-1.52 (br m, 10H), 1.63 (m, 1H), 2.20 (m, 1H), 2.81 (s, 6H), 3.06 (ABq, J=15.1 Hz, J=43.3 Hz, 2H), 3.16 (s, 6H), 3.76 (s, 6H), 4.11 (d, J=7.7 Hz, 1H), 5.09 (s, 2H), 5.14 (s, 2H), 5.48 (s, 1H), 5.96 (s, 1H), 6.49 (d, J=8.9 Hz, 1H), 6.99 (d, J=8.0 Hz, 2H), 7.26 (m, 1H), 7.44 (d, J=8.0 Hz, 2H), 7.52 (d, J=7.4 Hz, 2H), 7.68 (d, J=7.4 Hz, 2H), 7.87 (d, J=8.9 Hz, 1H); HRMS. Calc'd for C₄₀ H₅₆ N₃ O₄ S: 674.3992. Found: 674.4005.

Example 1426a ##STR507## (4R-cis)-1-[[4-[[4-[3,3-Dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4-hydroxy-1,1-dioxido-1-benzothiepin-5-yl]phenoxy]methyl]phenyl]methyl]-4-aza-1-azoniabicyclo[2.2.2]octane chloride

A solution of the chlorobenzyl intermediate (4.6 g, 7.7 mmol, obtained from Example 1425, Step 1) in acetonitrile (100 mL) at 25° C. under N₂ was treated with diazabicyclo[2.2.2]-octane (DABCO, 0.95 g, 8.5 mmol, 1.1 eq.) and stirred at 35° C. for 2 hours, during which time a white solid precipitated out. The white solid was collected, washed with CH₃ CN and recrystallized from CH₃ OH/Et₂ O to give the title compound (4.95 g, 91%) as a white solid: mp 223-230° C. (decomposed); ¹ H NMR (CDCl₃) δ0.89 (m, 6H), 1.27-1.52 (br m, 10H), 1.63 (m, 1H), 2.20 (m, 1H), 2.81 (s, 6H), 3.06 (ABq, J=15.1 Hz, J=43.3 Hz, 2H), 3.16 (s, 6H), 3.76 (s, 6H), 4.11 (d, J=7.7 Hz, 1H), 5.09 (s, 2H), 5.14 (s, 2H), 5.48 (s, 1H), 5.96 (s, 1H), 6.49 (d, J=8.9 Hz, 1H), 6.99 (d, J=8.0 Hz, 2H), 7.26 (m, 1H), 7.44 (d, J=8.0 Hz, 2H), 7.52 (d, J=7.4 Hz, 2H), 7.68 (d, J=7.4 Hz, 2H), 7.87 (d, J=8.9 Hz, 1H); HRMS. Calc'd for C₄₀ H₅₆ N₃ O₄ S: 674.3992. Found: 674.4005.

Example 1427 ##STR508## 4R-cis)-N-(Carboxymethyl)-N-[[4-[[4-[3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4-hydroxy-1,1-dioxido-1-benzothiepin-5-yl]phenoxy]methyl]phenyl]methyl]glycine

Step 1: Preparation of chlorobenzyl intermediate

To a stirred solution of 144 mg (3.59 mmol, 60% disp) of NaH in 29 mL of DMF was added 1.5 g (3.26 mmol) of 5-(4'-hydroxyphenyl)-7-(dimethylamino)tetrahydrobenzothiepine-1,1-dioxide (obtained from Example 1402, Step 10), and the resulting solution was stirred at ambient temperature for 45 min. To the solution was added 7.13 g (40.75 mmol) of dichloro p-xylene, and the mixture was stirred overnight. DMF was removed in vacuo, and the residue was extracted with ethyl acetate and washed with brine. The extract was dried over MgSO₄, and the concentrated residue was purified by column chromatography to give the chlorobenzyl intermediate: ¹ H NMR (CDCl₃) δ 0.90 (q, 6H), 1.05-1.65 (m, 11H), 2.2 (t, 1H), 2.8 (s, 6H), 3.0 (q, 2H), 4.1 (d, 1H), 4.6 (s, 2H), 5.1 (s,2H), 5.5 (s, 1H), 6.0 (s, 1H), 6.6 (d,1H), 7.0 (d, 2H), 7.4 (m, 6H), 7.8 (d,1H).

Step 2: Preparation of amino diester

A mixture of 1.03 g (1.72 mmol) of chlorobenzyl intermediate (obtained from Step 1), 1.63 g (8.6 mmol) of diethyl amino diacetate, and 0.72 g (8.6 mmol) of NaHCO₃ in 30 mL of DMF was stirred at 100° C. for 6 hours. DMF was removed in vacuo and the residue was extracted with ether and washed with brine. The extract was dried over MgSO₄, and the concentrated residue was purified by column chromatography to give amino diester intermediate: ¹ H NMR (CDCl₃) δ 0.90 (q, 6H), 1.05-1.65 (m, 17H), 2.2 (t, 1H), 2.8 (s, 6H), 3.0 (q, 2H), 3.55 (s, 4H), 3.95 (s, 2H), 4.1-4.2 (m, 5H), 5.05 (s, 2H), 5.42 (s, 1H), 5.95 (s, 1H), 6.5 (d, 1H), 7.0 (d, 2H), 7.4 (s, 6H), 7.8 (d, 1H).

Step 3: Preparation of amino diacid

A solution of 0.863 g (1.15 mmol) of dibenzyl ester (obtained from Step 2) and 0.232 g (5.52 mmol) of LiOH in 30 mL of THF and 30 mL of water was stirred at 40° C. under N₂ for 4 hours. The reaction mixture was diluted with ether and washed with 1% HCl. The aqueous layer was extracted twice with ether, and the combined extracts were washed with brine, dried over MgSO₄, and concentrated in vacuo to give the desired title compound as a solid: mp 175° C.; ¹ H NMR (THF-d8) 0.95 (q, 6H), 1.05-1.65 (m, 11H), 2.22 (t, 1H), 2.8 (s, 6H), 3.0 (t, 2H), 3.5 (s, 4H), 3.9 (s, 2H), 4.1 (d, 1H), 5.1 (s, 2H), 5.4 (s, 1H), 6.05 (s, 1H), 6.5 (d, 1H), 7.0 (d, 2H), 7.4 (m, 6H), 7.78 (d, 1H). HRMS. Calc'd for C₃₈ H₅₀ N₂ O₈ S: 695.3366. Found: 695.3359. Anal. Calc'd for C₃₈ H₅₀ N₂ O₈ S: C, 65.68; H, 7.25; N, 4.03; S, 4.61. Found: C, 64.95; H, 7.32; N, 3.94; S, 4.62.

Example 1428 ##STR509## (4R-cis)-4-[[4-[3,3-Dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4-hydroxy-1,1-dioxido-1,1-dioxido-1-benzothiepin-5-yl]phenoxy]methyl]-1-methylpyridinium salt with trifluoroacetic acid (1:1)

Step 1: Preparation of picolyl intermediate

To a stirred solution of 12.0 g (26.1 mmol) of 5-(4'-hydroxyphenyl)-7-(dimethylamino)tetrahydrobenzothiepine-1,1-dioxide (obtained from Example 1402, Step 10) in 200 mL of DMF was added 1.4 g (60% oil dispersion, 35 mmol) of sodium hydride and the reaction stirred at ambient temperature for one hour. 5.99 g (36.5 mmol) of 4-picolyl chloride hydrochloride was treated with cold saturated NaHCO₃ solution and extracted with diethyl ether. The ethereal extracts were washed with brine, dried over MgSO₄, and filtered. The reaction was cooled in an ice bath and the solution of 4-picolyl chloride in diethyl ether was added. The reaction was stirred at ambient temperature for 17 hours. The reaction was quenched with 25 mL of saturated NH₄ Cl, diluted with 600 mL ethyl acetate washed with 4×250 mL water, brine, dried over MgSO₄, filtered and concentrated in vacuo. Purification by silica gel chromatography (Waters-prep 500) using 60% ethyl acetate/hexanes afforded 11.05 g (77%) of the picolinyl intermediate as a colorless solid: mp 95-98° C.; ¹ H NMR (CDCl₃) δ 0.86-0.96 (m, 6H), 1.02-1.52 (m, 10H), 1.58-1.70 (m, 1H), 2.16-2.29 (m, 1H), 2.81 (s, 6H), 3.07 (AB_(q), J_(AB) =15.3, 49.6 Hz, 2H), 4.10 (d, J=7.5 Hz, 1H), 5.15 (s, 2H), 5.50 (s, 1H), 5.94 (d, J=2.7 Hz, 1H), 6.51 (dd, J=2.4, 8.7 Hz, 1H), 7.00 (d, J=9.0 Hz, 2H), 7.39 (d, 6.0 Hz, 2H), 7.44 (s, J=8.7 Hz, 2H), 7.89 (d, J=9.0 Hz, 2H), 8.63 (dd, J=1.6, 4.8 Hz, 2H).

Step 2: Preparation of quaternary salt

To a stirred solution of 0.41 g (0.74 mmol) of picolinyl intermediate (obtained from Step 1) in 10 mL of acetonitrile and 3 mL of dichloromethane was added 137 mg (0.97 mmol) of iodomethane. The reaction was stirred at ambient temperature for 16 hours, then concentrated under a nitrogen stream. Purification by reversed phase chromatography (Waters-Delta prep) using 60-55% water/acetonitrile afforded 0.304 g (60%) of the desired title compound as a colorless solid: mp 96-99° C.; ¹ H NMR (CDCl₃) δ 0.85-0.95 (m, 6H), 1. 03-1. 52 (m, 10H), 1.57-1.70 (m, 1H), 2.12-2.27 (m, 1H), 2.84 (s, 6H), 3.09 (AB_(q), J_(AB) =15.0, 27.9 Hz, 2H), 4.11 (s, 1H), 4.46 (s, 3H), 5.37 (s, 2H), 5.50 (s, 1H), 6.07 (d, J=2.4 Hz, 1H), 6.61 (dd, J=2.5, 8.7 Hz, 1H), 7.02 (d, J=8.7 Hz, 2H), 7.48 (d, J=7.2 Hz, 2H), 7.90 (d, J=8.7 Hz, 1H), 8.14 (d, J=6.3 Hz, 2H), 8.80 (d, J=6.6 Hz, 2H). HRMS Calc'd for C₃₃ H₄₅ N₂ O₄ S: 565.3100. Found: 565.3125.

Example 1429 ##STR510## (4R-cis)-4-[[4-[3,3-Dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4-hydroxy-1,1-dioxido-1,1-dioxido-1-benzothiepin-5-yl]phenoxy]methyl]-1-methylpyridinium, methanesulfonate (salt)

To a stirred solution of 6.5 g (11.8 mmol) of picolyl intermediate (obtained from Example 1428, Step 1) in 140 mL of acetonitrile heated at 70° C. was added 1.56 g (14.6 mmol) methanesulfonic acid methyl ester. Heating was continued at 70° C. for 15 hours. The reaction was cooled and diluted with 50 mL of ethyl acetate. The solid was collected by vacuum filtration to give 6.14 g (79%). The filtrate was concentrated in vacuo and the residue crystallized from hot acetonitrile to give 1.09 g (14%). A total of 7.23 g (93%) of the desired title compound was obtained as an off-white solid: mp 232-233.5° C.; ¹ H NMR (CDCl₃) δ 0.66-0.76 (m, 6H), 0.85-0.95 (m, 1H), 0.95-1.35 (m, 9H), 1.42-1.54 (m, 1H), 1.95-2.22 (m, 1H), 2.50 (s, 1H), 2.56 (s, 3H), 2.63 (s, 6H), 2.91 (AB_(q), J=16.5, 24.0 Hz, 2H), 3.88 (s, 1H), 4.40 (s, 3H), 5.21 (s, 3H), 5.78 (d, J=2.4 Hz, 1H), 6.31 (dd, J=2.5, 8.7 Hz, 1H), 6.84 (d, J=8.7 Hz, 2H), 7.31 (d, J=8.4 Hz, 2H), 7.64 (d, J=8.7 Hz, 1H), 8.0 (d, J=6.6 Hz, 2H), 9.02 (d, J=6.6 Hz, 2H). HRMS Calc'd for C₃₃ H₄₅ N₂ O₄ S: 565.3100. Found: 656.3087. Anal. Calc'd for C₃₄ H₄₈ N₂ O₇ S₂ : C, 61.79; H, 7.32; N, 4.24; S, 9.70. Found: C, 61.38, H, 7.47; N, 4.22; S, 9.95.

Example 1430 ##STR511## (4R-cis)-6-[[4-[3, 3-Dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4-hydroxy-1,1-dioxido-1-benzothiepin-5-yl]phenoxy]methyl]-2-pyridinepropanoic acid

Step 1: Preparation of picolinyl chloride intermediate

To a solution of 5-(4'-hydroxyphenyl)-7-(dimethylamino)tetrahydrobenzothiepine-1,1-dioxide (1 g, 2.1 mmol, obtained from Example 1402, Step 10) in acetone (50 mL) was added anhydrous K₂ CO₃ (0.45 g, 3.2 mmol), tetrabutylammonium iodide (0.1 g, 0.2 mmol) and 2,6-bischloromethylpyridine (1.2 g, 10.8 mmol). The flask was equipped with nitrogen gas adapter and magnetic stirrer. The reaction was heated to reflux for overnight. After 18 hours, the reaction was diluted with ether and washed with water and brine (30 mL). The organic layers were dried over MgSO₄, filtered and concentrated in vacuo. Chromatographic purification through silica gel, eluting with 25% EtOAc/Hexane gave 0.75 g (55%) of the picolyl chloride intermediate as an oil (0.70 g, 55%): ¹ H NMR (CDCl₃) δ0.84-0.95 (m, 6H), 1.02-1.5 (m, 10H), 1.56-1.66 (m, 1H), 2.14-2.24 (m, 1H), 2.80 (s, 6H) 3.05 (ABq, 2H), 4.10 (d, 2H), 4.65 (s, 2H), 5.20 (s, 2H), 5.45 (s, 1H), 5.95 (s, 1H), 6.50 (d, 1H), 7.0 (d, 2H),7.35-7.50 (m, 4H), 7.70-7.85 (m, 2H).

Step 2: Preparation of pyridinyl malonate intermediate

Dibenzyl malonate (1.42 g, 5.01 mmol) in DMF (20.0 mL) and sodium hydride (0.13 g, 3.3 mmol) were placed in a dry three-neck flask. The flask was equipped with nitrogen gas adapter and magnetic stirrer. The picolyl chloride intermediate (1 g, 1.67 mmol) was added and heated at 90° C. for overnight. The reaction was cooled and extracted with 5% HCl with methylene chloride and washed with water (25 mL), and brine (50 mL). The organic layers were dried over MgSO₄, filtered and concentrated. The residue was purified by C-18 reversed phase column eluting with 50% acetonitrile/water and gave pyridinyl malonate intermediate as a white foamy solid (1 g, 71%): ¹ H NMR (CDCl₃) δ 0.84-0.95 (m, 6H), 1.02-1.5 (m, 10H), 1.56-1.66 (m, 1H), 2.14-2.24 (m, 1H), 2.80 (s, 6H) 3.05 (ABq, 2H), 3.22 (d, 2H), 4.05 (d, 1H), 4.16 (t, 1H), 5.02(s, 2H), 5.08 (s, 4H), 5.44 (s, 1H), 5.97 (s, 1H), 6.96-7.10 (m, 3H), 7.20-7.32 (m, 12H), 7.5 (t, 1H), 7.9 (d, 1H).

Step 3: Preparation of pyridinyl acid

The pyridinyl malonate intermediate (0.6 g, 0.7 mmol, obtained from Step 2), THF/water (25.0 mL, 1:1) and lithium hydroxide monohydrate (0.14 g, 3.4 mmol) were placed in a 100 mL round-bottom flask. The reaction was stirred at ambient temperature overnight. After 18 hours, the reaction was extracted with 1% HCl and ether and then washed with water (20 mL) and brine (30 mL). The organic layers were dried over MgSO₄, filtered and concentrated in vacuo gave the desired title compound as a white solid (0.44 g, 90%): mp 105-107° C.; ¹ H NMR (CDCl₃) δ 0.84-0.95 (m, 6H), 1.02-1.5 (m, 10H), 1.56-1.66 (m, 1H), 2.14-2.24 (m, 1H), 2.80 (s, 6H),3.05 (m, 2H), 3.10 (ABq, 2H), 3.22 (m, 2H), 4.05 (s, 1H), 5.30 (s, 2H), 5.50 (s, 1H), 5.97 (s, 1H), 6.50 (d, 1H), 7.02 (d, 2H), 7.3 (d, 1H), 7.42 (d, 2H), 7.58 (d, 1H), 7.8-7.9 (m, 2H). HRMS. Calc'd for C₃₅ H₄₆ N₂ O₆ S: 623.3155. Found: 623.3188.

Example 1431 ##STR512## (4R-cis)-N-(Carboxymethyl)-N-[[6-[[4-[3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4-hydroxy-1,1-dioxido-1-benzothiepin-5-yl]phenoxy]methyl]-2-pyridinyl]methyl]glycine

Step 1: Preparation of pyridinyl diester intermediate

A mixture of diethyl aminodiacetate (8 g, 68 mmol) and sodium carbonate (0.63 g, 5.9 mmol) was treated with picolyl chloride intermediate (0.72 g, 1.2 mmol, obtained from Example 1430, Step 1), and stirred at 160° C. for three hours. The reaction was cooled and diluted with ether and washed with 1% HCl, water (25 mL), and brine (50 mL). The combined extracts were dried over MgSO₄, filtered and concentrated in vacuo. The residue was purified by distillation in the Kugelrohr to give pyridinyl diester intermediate as a yellowish foamy solid (0.72 g, 80%): ¹ H NMR (CDCl₃) δ 0.84-0.95 (m, 6H), 1.02-1.5 (m, 16H), 1.56-1.66 (m, 1H), 2.14-2.24 (m, 1H), 2.80 (s, 6H) 3.05 (ABq, 2H), 3.70 (s, 4H), 4.2-4.4 (m, 6H), 5.30 (s, 2H), 5.56 (s, 1H),6.02 (s, 1H), 6.60 (d, 1H), 7.10 (d, 2H),7.50 (m, 3H), 7.61 (d, 1H), 7.80 (t, 1H), 7.95 (d, 1H). HRMS. Calc'd for C₄₁ H₅₇ N₃ O₈ S: 752.3945. Found: 752.3948.

Step 2: Preparation of pyridinyl diacid

A mixture of pyridine-aminodiacetate intermediate (0.7 g, 0.93 mmol, obtained from Step 1), and lithium hydroxide monohydrate (0.18 g, 4.5 mmol) in THF/water (25.0 mL, 1:1) was stirred at 40° C. overnight (18 hours). The reaction mixture was diluted with ether and washed with 1% HCl, water (20 mL), and brine (30 mL). The organic layers were dried over MgSO₄, filtered and concentrated in vacuo to give the desired title compound as a white solid (0.44 g, 90%): mp 153-155° C.; ¹ H NMR (CDCl₃) δ 0.84-0.95 (m, 6H), 1.02-1.5 (m, 10H), 1.56-1.66 (m, 1H), 2.14-2.24 (m, 1H), 2.80 (s, 6H), 3.10 (ABq, 2H), 3.90 (m, 3H), 4.05 (s, 1H), 4.40 (s, 2H), 5.20 (s, 2H), 5.50 (s, 1H), 5.97 (s, 1H), 6.50 (d, 1H), 7.02 (d, 2H), 7.3 (d, 1H), 7.42 (d, 2H), 7.58 (d, 1H), 7.8-7.9 (m, 2H). HRMS. Calc'd for C₃₇ H₄₉ N₃ O₈ S: 696.3319. Found:696.3331.

Example 1432 ##STR513## (4S-cis)-[2-[2-[4-[3,3-Dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4-hydroxy-1,1-dioxido-1-benzothiepin-5-yl]phenoxy]ethoxy]ethyl]propanedioic acid

Step 1: Preparation of bromoethyl ether intermediate

To a stirred solution of 0.192 g (4.785 mmol, 60% disp) of NaH in 28 mL of DMF was added 2.0 g (4.35 mmol) of 5-(4'-hydroxyphenyl)-7-(dimethylamino)tetrahydrobenzothiepine-1,1-dioxide (obtained from Example 1402, Step 10), and the resulting solution was stirred at ambient temperature for 30 min. To the solution was added 13.2 g (54.38 mmol) of bis(2-bromoethyl)ether, and stirring was continued at ambient temperature under N₂ overnight. DMF was removed in vacuo and the residue was extracted with ethyl acetate and washed with brine. The extract was dried over MgSO₄, and the concentrated residue was purified by column chromatography to give bromoethyl ether intermediate: ¹ H NMR (CDCl₃) δ 0.90 (q, 6h), 1.05-1.65 (m, 11H), 2.2 (t, 1H), 2.8 (s, 6H), 3.0 (q, 2H), 3.5 (t, 2H), 3.9 (m, 4H), 4.1 (d, 1H), 4.2 (d, 2H), 5.42 (s, 1H), 5.95 (s, 1H), 6.5 (d, 1H), 6.95 (d, 2H), 7.4 (d, 2H), 7.9 (d, 1H).

Step 2: Preparation of diester intermediate

To a mixture of 94 mg (2.34 mmol, 60% disp) of NaH in 45 mL of THF and 15 mL of DMF at 0° C. was added 1.33 g (4.68 mmol) of dibenzyl malonate (Aldrich), and the resulting solution was stirred at ambient temperature for 15 min, followed by the addition of 0.95 g (1.56 mmol) of bromoethyl ether intermediate (obtained from Step 1). The mixture was stirred under N₂ at 80° C. overnight. Solvent was removed in vacuo and the residue was extracted with methylene chloride and washed with brine. The extract was dried over MgSO₄, and the concentrated residue was purified by column chromatography to give the diester intermediate: ¹ H NMR (CDCl₃) δ 0.90 (q, 6H), 1.05-1.65 (m, l1H), 2.2-2.3 (m, 3H), 2.8 (s, 6H), 3.0 (q, 2H), 3.6 (t, 2H), 3.7 (m, 3H), 4.1 (m, 3H), 5.1 (s, 4H), 5.42 (s, 1H), 5.9 (s, 1H), 6.5 (d, 1H), 6.9 (d, 2H), 7.3 (m, 10H), 7.4 (d, 2H), 7.9 (d, 1H).

Step 3: Preparation of diacid

A suspension of 0.761 g (0.935 mmol) of the diester intermediate (obtained from Step 2) and 35 mg of 10% Pd/C in 25 mL of ethanol and 5 mL of THF was agitated at ambient temperature under 20 psi of hydrogen gas for 2 hours. The catalyst was filtered off, and the filtrate was concentrated to give the desired title compound as a solid: mp 119.5° C.; ¹ H NMR (THF-d8) 0.95 (q, 6H), 1.05-1.65 (m, 11H), 2.1 (q, 2H), 2.25 (t, 1H), 2.8 (s, 6H), 3.0 (t, 2H), 3.47 (q, 2H), 3.58 (s, 1H), 3.78 (t, 2H), 4.08 (d, 1H), 4.15 (t, 2H), 5.4 (s, 1H), 6.05 (s, 1H), 6.55 (d, 1H), 6.98 (d, 2H), 7.42 (d, 2H), 7.8 (d, 1H). HRMS. Calc'd for C₃₃ H₄₇ NO₉ S: 632.2893. Found: 632.2882. Anal. Calc'd for C₃₃ H₄₇ NO₉ S: C, 62.54; H, 7.47; N, 2.21; S, 5.06. Found: C, 61.75; H, 7.56; N, 2.13; S, 4.92.

Example 1433 ##STR514## (4R-cis)-a-[[4-[3,3-Dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4-hydroxy-1,1-dioxido-1-benzothiepin-5-yl]phenoxy]methyl]-w-methoxypoly(oxy-1,2-ethanediyl)

Step 1: Preparation of monomethyl PEG mesylate intermediate

To a solution of 20 g of monomethyl ether PEG in 100 mL of methylene chloride was added 2.2 g (22 mmol) of triethyl amine, and to the resulting solution at 0° C. was added dropwise 2.5 g (22 mmol) of methanesulfonyl chloride. The resulting solution was stirred overnight at ambient temperature, and the triethyl amine hydrochloride was filtered off to give the monomethyl PEG mesylate intermediate which was used in the next Step without further purification and characterization.

Step 2: Preparation of polyethylene-linked benzothiepene

A mixture of 38 mg (1.52 mmol 95%) of NaH and 0.7 g (1.52 mmol) of 5-(4'-hydroxyphenyl)-7-(dimethylamino)tetrahydrobenzothiepine-1,1-dioxide (obtained from Example 1402, Step 10) in 5.5 mL of DMF was stirred at ambient temperature under N₂ for 30 min. To the solution was added 0.55 g (0.51 mmol) of the mesylate PEG intermediate (obtained from Step 1) in 5.5 mL of DMF, and the resulting solution was stirred overnight under N₂ at 50° C. DMF was removed in vacuo and the residue was extracted with methylene chloride and washed with brine. The extract was dried over MgSO₄, and the concentrated residue was purified by column chromatography to give the desired title compound as an oil: ¹ H NMR (CDCl₃) δ 0.9 (q, 6h), 1.05-1.65 (m, 11H), 2.2 (t, 1H), 2.8 (s, 6H), 3.0 (q, 2H), 3.4 (s, 4H), 3.5-3.85 (m, 95H), 4.1 (s, 1H), 4.15 (t, 2H), 5.5 (s, 1H), 6.05 (s, 1H), 6.6 (d, 1H), 6.9 (d, 2H), 7.4 (d, 2H), 7.9 (d, 1H).

Example 1434

Preparation of ##STR515##

The 3-aminobenzothiepene prepared in Step 5 of Example 1398 (0.380 g, 0.828 mmol), sodium hydroxide (0.35 mL, 0.875 mmol, 10% in H₂ O) and toluene (0.50 mL) were combined in a 10 mL round-bottom flask. The reaction flask was purged with N₂, equipped with magnetic stirrer, and cooled to 0° C. A solution of 3-chloropropyl chloroformate (1.440 g, 1.10 mmol, 12% in CH₂ Cl₂ /THF) was added. After 3.5 hrs, toluene (3.0 mL) was added, and the mixture was washed with H₂ O (2×4 mL), dried (MgSO₄), filtered and concentrated in vacuo. Purification by flash chromatography on silica gel eluting with 20% EtOAc/hexane and concentrated in vacuo gave a white solid (0.269 g, 56%). ¹ H NMR (CDCl₃) δ0.87-0.93 (m, 6H), 1.05-1.70 (m, 11H), 2.14 (t, J=6.3 Hz, 2H), 2.15-2.25 (m, 1H), 2.81 (s, 6H), 3.07 (ABq, 2H), 3.64 (t, J=6.3 Hz, 2H), 4.11 (d, J=7.5 Hz, 1H), 4.33 (t, J=6.0 Hz, 2H), 5.50 (s, 1H), 5.99 (d, J=2.4 Hz, 1H), 6.51 (dd, J=9.0, 2.7 Hz, 1H), 6.65 (s, 1H), 7.23 (d, J=7.8 Hz, 1H), 7.34-7.39 (m, 2H), 7.54 (d, J=7.2 Hz, 1H), 7.89 (d, 8.7 Hz, 1H). HRMS (M+H). Calc'd for C₃₀ H₄₄ N₂ O₅ SCl: 579.2659. Found: 579.2691.

Example 1435

Preparation of ##STR516##

1,4-Diazabicyclo(2.2.2)octane (0.0785 g, 0.700 mmol) and acetonitrile (1.0 mL) were combined in a 10 mL round-bottom flask. The reaction flask was purged with N₂, equipped with magnetic stirrer, and heated to 37° C. A solution of the product of Example 1434 (0.250 g, 0.432 mmol) in acetonitrile (2.50 mL) was added. After 2.5 hrs, 1,4-diazabicyclo(2.2.2)octane (0.0200 g, 0.178 mmol) was added. After 64 hrs, 1,4-diazabicyclo(2.2.2)octane (0.0490 g, 0.437 mmol) was added. After 24 hrs, the reaction mixture was cooled to R.T. and concentrated in vacuo. The crude product was dissolved in acetonitrile (2.0 mL) and precipitated with ethyl ether (10.0 mL). The precipitate was filtered to yield a white solid. This trituration method was repeated, followed by concentrated in vacuo to give a white solid (0.185 g, 62%). mp 218.0-225.0° C.; ¹ H NMR (CD₃ OD) δ 0.90 (m, 6H), 1.05-1.55 (m, 10H), 1.16 (t, J=6.6 Hz, 2H), 1.78 (m, 1H), 2.12 (m, 3H), 2.76 (s, 6H), 3.10 (m, 2H), 3.17 (t, J=7.2 Hz, 6H), 3.30-3.50 (m, 8H), 4.10 (s, 1H), 4.21 (t, J=5.4 Hz, 2H), 5.31 (s, 1H), 6.10 (s, 1H), 6.55 (d, J=7.2 Hz, 1H), 7.25 (d, J=6.9 Hz, 1H), 7.33-7.42 (m, 2H), 7.56 (s, 1H), 7.76 (d, J=9.0 Hz, 1H). HRMS. Calc'd for C₃₆ H₅₅ N₄ O₅ SCl: 655.3893. Found: 655.3880.

Example 1436

Preparation of ##STR517## Step 1. Preparation of ##STR518##

3-Chloromethylbenzoyl chloride (2.25 mL/15.8 mmol) and acetone (8.0 mL) were combined in a 25 mL round-bottom flask. The reaction flask was cooled to 0° C., and an aqueous solution of sodium azide (1.56 g in 5.50 mL/24.0 mmol) was added. After 1.5 hrs, the reaction mixture was poured into ice water (80.0 mL), extracted with ethyl ether (2×25 mL), dried (MgSO₄), and concentrated in vacuo to give a colorless oil (2.660 g, 86%). ¹ H NMR (CDCl₃) δ 4.62 (s, 2H), 7.47 (t, J=7.8 Hz, 1H), 7.66 (d, J=7.8 Hz, 1H), 7.99 (d, J=7.8 Hz, 1H), 8.05 (s, 1H).

Step 2

3-Chloromethylbenzoyl azide (0.142 g, 0.726 mmol) and toluene (2.0 mL) were combined in a 10 mL round-bottom flask. The reaction flask was purged with N₂, equipped with magnetic stirrer, and heated to 110° C. After 2 hrs, the reaction mixture was cooled to R.T, and the 3-aminobenzothiepene prepared in Step 5 of Example 1398 (0.365 g, 0.796 mmol) was added. After 2.25 hrs, the mixture was heated to 50° C. After 0.75 hrs, 3-chloromethylbenzoyl azide (0.025 g, 0.128 mmol) was added, and the reaction mixture was heated to reflux. After 0.5 hrs, the reaction mixture was cooled to R.T. and concentrated in vacuo. Purification by flash chromatography on silica gel eluting with 20-30% EtOAc/hexane and concentrated in vacuo gave a white foamy solid (0.309 g, 62%). ¹ H NMR (CDCl₃) δ 0.71 (t, J=5.4 Hz, 3H), 0.88 (t, J=6.3 Hz, 3H), 1.03-1.60 (m, 11H), 1.85 (d, 6.3 Hz, 1H), 2.27 (m, 1H), 2.76 (s, 6H), 3.15 (t, 2H), 4.17 (d, J=6.6 Hz, 1H), 4.48 (s, 2H), 5.42 (s, 1H), 6.07 (s, 1H), 6.99 (d, J=7.5 Hz), 7.18-7.26 (m, 2H), 7.30-7.41 (m, 3H), 7.63 (s, 1H), 7.86 (d, J=9.0 Hz, 2H), 7.96 (s, 1H), 8.17 (s, 1H). HRMS (M+Li). Calculated for C₃₄ H₄₄ N₃ O₄ SClLi: 632.2901. Found: 632.2889.

Example 1437

Preparation of ##STR519##

1,4-Diazabicyclo(2.2.2)octane (0.157 g, 1.40 mmol) and acetonitrile (1.00 mL) were combined in a 10 mL round-bottom flask. The reaction flask was purged with N₂ and equipped with magnetic stirrer. A solution of the product of Example 1436 (0.262 g, 0.418 mmol) in acetonitrile (2.70 mL) was added. After 2.5 hrs, a white precipitate had had formed. Ethyl ether (6.0 mL) was added, and the precipitate was filtered, washed with ethyl ether, and dried in vacuo to yield a white solid (0.250 g, 80%). mp 246.0-248.0° C.; ¹ H NMR (CD₃ OD) δ 0.88 (m, 6H), 1.03-1.55 (m, 10H), 1.76 (m, 1H), 2.11 (m, 1H), 2.74 (s, 6H), 3.11 (m, 8H), 3.37 (m, 6H), 4.12 (s, 1H), 4.39 (s, 2H), 5.31 (s, 1H), 6.11 (s, 1H), 6.52 (dd, J=8.7, 1.8 Hz, 1H), 7.09 (d, J=7.2 Hz, 1H), 7.23 (d, J=6.9 Hz, 1H), 7.32-7.38 (m, 2H), 7.47 (m, 2H), 7.58 (s, 1H), 7.73 (d, J=8.7 Hz, 2H). HRMS. Calculated for C₄₀ H₅₆ N₅ O₄ SCl: 702.4053. Found: 702.4064. Anal. Calculated for C₄₀ H₅₆ N₅ O₄ SCl: C, 65.06; H, 7.64; N, 9.48; S, 4.34; Cl, 4.80. Found: C, 64.90; H, 7.77; N, 9.42; S, 4.16; Cl, 4.89.

Examples 1438-1454

The compounds of Examples 1438 through 1454 can be prepared in accordance with one or more of the synthetic schemes previously disclosed in this application or using methods known to those skilled in the art.

    ______________________________________                                          ##STR520##                                                                           R.sup.5m                                                                ______________________________________                                         1438.                                                                                    ##STR521##                                                           1439.                                                                                    ##STR522##                                                           1440.                                                                                    ##STR523##                                                           1441.                                                                                    ##STR524##                                                           1442.                                                                                    ##STR525##                                                           1443.                                                                                    ##STR526##                                                           1444.                                                                                    ##STR527##                                                           1445.                                                                                    ##STR528##                                                           1446.                                                                                    ##STR529##                                                           1446.                                                                                    ##STR530##                                                           1447.                                                                                    ##STR531##                                                           1448.                                                                                    ##STR532##                                                           1449.                                                                                    ##STR533##                                                           1450.                                                                                    ##STR534##                                                           1451.                                                                                    ##STR535##                                                           1452.                                                                                    ##STR536##                                                           1453.                                                                                    ##STR537##                                                           1454.                                                                                    ##STR538##                                                           ______________________________________                                    

Example 1455 ##STR539##

The 3-aminobenzothiepine of step 5 of Example 1398 (0.0165 g/0.0360 mmol), M-NCO-5000 (0.150 g/0.30 mmol) (Methoxy-PEG-NCO, MW 5000, purchased from Shearwater Polymers Inc., 2130 Memorial Parkway, SW, Huntsville, Ala. 35801), and CDCl₃ (0.7 mL) were combined in an 8 mm NMR tube. The tube was purged with N₂. After 72 hrs, the reaction mixture was heated to 50° C. After 24 hrs, an additional aliquot of the 3-aminobenzothiepine of step 5 of Example 1398 (0.0077 g/0.017 mmol) was added. After 24 hrs, the reaction mixture was transferred to a 2 mL vial and evaporated to dryness with a N₂ purge. The resulting white solid was dissolved in hot ethyl ether (2.0 mL) and ethyl acetate (0.057 mL/4 drops), cooled to precipitate and filtered. This precipitation procedure was repeated until no starting material was detected in the precipitate (TLC: SiO₂ /80% EtOAc/hexanes). Concentrated in vacuo to give a white solid (0.0838 g/51%). ¹ H NMR (CDCl₃) d 0.82-0.90 (m, 6H), 1.05-1.49 (m, 14H), 1.18 (t, J=6.8 Hz, 2H), 1.59 (bt, 1H), 2.18 (bt, 1H), 2.34 (s, 2H), 2.78 (s, 6H), 3.04 (ABq, 2H), 3.35-3.80 (m, 625H), 4.09 (d, J=7.2 Hz, 2H), 5.42 (s, 1H), 5.78 (S, 1H), 6.04 (d, J=1.6 Hz, 1H), 6.47 (dd, J=6.4, 3.2 Hz, 1H), 7.07 (d, J=7.6 Hz, 1H), 7.31 (bs, 1H), 7.60 (d, J=7.6 Hz, 1H), 7.66 (s, 1H), 7.85 (d, J=8.8 Hz, 1H). Mass spectroscopy data also verified desired product.

Biological Assays

The utility of the compounds of the present invention is shown by the following assays. These assays are performed in vitro and in animal models essentially using a procedure recognized to show the utility of the present invention.

In Vitro Assay of compounds that inhibit IBAT-mediated uptake of [¹⁴ C]-Taurocholate (TC) in H14 Cells

Baby hamster kidney cells (BHK) transfected with the cDNA of human IBAT (H14 cells) are seeded at 60,000 cells/well in 96 well Top-Count tissue culture plates for assays run within in 24 hours of seeding, 30,000 cells/well for assays run within 48 hours, and 10,000 cells/well for assays run within 72 hours.

On the day of assay, the cell monolayer is gently washed once with 100 μl assay buffer (Dulbecco's Modified Eagle's medium with 4.5 g/L glucose+0.2% (w/v) fatty acid free bovine serum albumin-(FAF)BSA). To each well 50 μl of a two-fold concentrate of test compound in assay buffer is added along with 50 μl of 6 μM [¹⁴ C]-taurocholate in assay buffer (final concentration of 3 μM [¹⁴ C]-taurocholate). The cell culture plates are incubated 2 hours at 37° C. prior to gently washing each well twice with 100 μl 4° C. Dulbecco's phosphate-buffered saline (PBS) containing 0.2% (w/v) (FAF)BSA. The wells are then gently washed once with 100 μl 4° C. PBS without (FAF)BSA. To each 200 μl of liquid scintillation counting fluid is added, the plates are heat sealed and shaken for 30 minutes at room temperature prior to measuring the amount of radioactivity in each well on a Packard Top-Count instrument.

In Vitro Assay of compounds that inhibit uptake of [¹⁴ C]-Alanine

The alanine uptake assay is performed in an identical fashion to the taurocholate assay, with the exception that labeled alanine is substituted for the labeled taurocholate.

In Vivo Assay of compounds that inhibit Rat Ileal uptake of [¹⁴ C]-Taurocholate into Bile

(See "Metabolism of 3α,7β-dihydroxy-7α-methyl-5β-cholanoic acid and 3α,7β-dihydroxy-7α-methyl-5β-cholanoic acid in hamsters" in Biochimica et Biophysica Acta 833 (1985) 196-202 by Une et al.)

Male wistar rats (200-300 g) are anesthetized with inactin @100 mg/kg. Bile ducts are cannulated with a 10" length of PE10 tubing. The small intestine is exposed and laid out on a gauze pad. A canulae (1/8" luer lock, tapered female adapter) is inserted at 12 cm from the junction of the small intestine and the cecum. A slit is cut at 4 cm from this same junction (utilizing a 8 cm length of ileum). 20 ml of warm Dulbecco's phosphate buffered saline, pH 6.5 (PBS) is used to flush out the intestine segment. The distal opening is cannulated with a 20 cm length of silicone tubing (0.02" I.D.×0.037" O.D.). The proximal cannulae is hooked up to a peristaltic pump and the intestine is washed for 20 min with warm PBS at 0.25 ml/min. Temperature of the gut segment is monitored continuously. At the start of the experiment, 2.0 ml of control sample ([¹⁴ C]-taurocholate @ 0.05 mi/ml with 5 mM cold taurocholate) is loaded into the gut segment with a 3 ml syringe and bile sample collection is begun. Control sample is infused at a rate of 0.25 ml/min for 21 min. Bile samples fractions are collected every 3 minute for the first 27 minutes of the procedure. After the 21 min of sample infusion, the ileal loop is washed out with 20 ml of warm PBS (using a 30 ml syringe), and then the loop is washed out for 21 min with warm PBS at 0.25 ml/min. A second perfusion is initiated as described above but this with test compound being administered as well (21 min administration followed by 21 min of wash out) and bile sampled every 3 min for the first 27 min. If necessary, a third perfusion is performed as above that typically contains the control sample.

Measurement of Hepatic Cholesterol Concentration (HEPATIC CHOL)

Liver tissue was weighed and homogenized in chloroform:methanol (2:1). After homogenization and centrifugation the supernatant was separated and dried under nitrogen. The residue was dissolved in isopropanol and the cholesterol content was measured enzymatically, using a combination of cholesterol oxidase and peroxidase, as described by Allain, C. A., et al. (1974) Clin. Chem. 20, 470.

Measurement of Hepatic HMG CoA-Reductase Activity (HMG COA)

Hepatic microsomes were prepared by homogenizing liver samples in a phosphate/sucrose buffer, followed by centrifugal separation. The final pelleted material was resuspended in buffer and an aliquot was assayed for HMG CoA reductase activity by incubating for 60 minutes at 37° C. in the presence of ¹⁴ C-HMG-CoA (Dupont-NEN). The reaction was stopped by adding 6N HCl followed by centrifugation. An aliquot of the supernatant was separated, by thin-layer chromatography, and the spot corresponding to the enzyme product was scraped off the plate, extracted and radioactivity was determined by scintillation counting. (Reference: Akerlund, J. and Bjorkhem, I. (1990) J. Lipid Res. 31, 2159).

Determination of Serum Cholesterol (SER.CHOL, HDL-CHOL, TGI and VLDL+LDL)

Total serum cholesterol (SER.CHOL) was measured enzymatically using a commercial kit from Wako Fine Chemicals (Richmond, Va.); Cholesterol C11, Catalog No. 276-64909. HDL cholesterol (HDL-CHOL) was assayed using this same kit after precipitation of VLDL and LDL with Sigma Chemical Co. HDL Cholesterol reagent, Catalog No. 352-3 (dextran sulfate method). Total serum triglycerides (blanked) (TGI) were assayed enzymatically with Sigma Chemical Co. GPO-Trinder, Catalog No. 337-B. VLDL and LDL (VLDL+LDL) cholesterol concentrations were calculated as the difference between total and HDL cholesterol.

Measurement of Hepatic Cholesterol 7-α-Hydroxylase Activity (7a-OHase)

Hepatic microsomes were prepared by homogenizing liver samples in a phosphate/sucrose buffer, followed by centrifugal separation. The final pelleted material was resuspended in buffer and an aliquot was assayed for cholesterol 7-α-hydroxylase activity by incubating for 5 minutes at 37° C. in the presence of NADPH. Following extraction into petroleum ether, the organic solvent was evaporated and the residue was dissolved in acetonitrile/methanol. The enzymatic product was separated by injecting an aliquot of the extract onto a C₁₈ reversed phase HPLC column and quantitating the eluted material using UV detection at 240 nm. (Reference: Horton, J. D., et al. (1994) J. Clin. Invest. 93, 2084).

Rat Gavage Assay

Male Wister rats (275-300 g) are administered IBAT inhibitors using an oral gavage procedure. Drug or vehicle (0.2% Tween 80 in water) is administered once a day (9:00-10:0 a.m.) for 4 days at varying dosages in a final volume of 2 mL per kilogram of body weight. Total fecal samples are collected during the final 48 hours of the treatment period and analyzed for bile acid content using an enzymatic assay as described below. Compound efficacy is determined by comparison of the increase in fecal bile acid (FBA) concentration in treated rats to the mean FBA concentration of rats in the vehicle group.

Measurement of Fecal Bile Acid Concentration (FBA)

Total fecal output from individually housed hamsters was collected for 24 or 48 hours, dried under a stream of nitrogen, pulverized and weighed. Approximately 0.1 gram was weighed out and extracted into an organic solvent (butanol/water). Following separation and drying, the residue was dissolved in methanol and the amount of bile acid present was measured enzymatically using the 3α-hydroxysteroid steroid dehydrogenase reaction with bile acids to reduce NAD. (Reference: Mashige, F., et al. (1981) Clin. Chem. 27, 1352).

[³ H]taurocholate Uptake in Rabbit Brush Border Membrane Vesicles (BBMV)

Rabbit Ileal brush border membranes were prepared from frozen ileal mucosa by the calcium precipitation method describe by Malathi et al. (Reference: (1979) Biochimica Biophysica Acta, 554, 259). The method for measuring taurocholate was essentially as described by Kramer et al. (Reference: (1992) Biochimica Biophysica Acta, 1111, 93) except the assay volume was 200 μl instead of 100 μl. Briefly, at room temperature a 190 μl solution containing 2 μM [³ H]-taurocholate(0.75 μCi), 20 mM tris, 100 mM NaCl, 100 mM mannitol pH 7.4 was incubated for 5 sec with 10 μl of brush border membrane vesicles (60-120 μg protein). The incubation was initiated by the addition of the BBMV while vortexing and the reaction was stopped by the addition of 5 ml of ice cold buffer (20 mM Hepes-tris, 150 mM KCl) followed immediately by filtration through a nylon filter (0.2 μm pore) and an additional 5 ml wash with stop buffer.

Acyl-CoA;cholesterol Acyl Transferase (ACAT)

Hamster liver and rat intestinal microsomes were prepared from tissue as described previously (Reference: (1980) J. Biol. Chem. 255, 9098) and used as a source of ACAT enzyme. The assay consisted of a 2.0 ml incubation containing 24 μM Oleoyl-CoA (0.05 μCi) in a 50 mM sodium phosphate, 2 mM DTT ph 7.4 buffer containing 0.25% BSA and 200 μg of microsomal protein. The assay was initiated by the addition of oleoyl-CoA. The reaction went for 5 min at 37° C. and was terminated by the addition of 8.0 ml of chloroform/methanol (2:1). To the extraction was added 125 μg of cholesterol oleate in chloroform methanol to act as a carrier and the organic and aqueous phases of the extraction were separated by centrifugation after thorough vortexing. The chloroform phase was taken to dryness and then spotted on a silica gel 60 TLC plate and developed in hexane/ethyl ether (9:1). The amount of cholesterol ester formed was determined by measuring the amount of radioactivity incorporated into the cholesterol oleate spot on the TLC plate with a Packard instaimager.

Data from each of the noted compounds in the assays described above is as set forth in TABLES 5, 6, 7, and 8 as follows:

                  TABLE 5                                                          ______________________________________                                                                             % of Control                                              In vitro % % Inhibition                                                                             Transport                                                 Inhibition of                                                                             of Alanine                                                                               of TC in                                   COM-    IC50   TC Uptake @                                                                               Uptake @  Rat Ileum @                                POUND   uM*    100 uM #   100 uM #  0.1 mM #                                   ______________________________________                                         Benzothiaze                                                                            2                 0         45.4 +/- 0.7                               pine=                                                                          12             25                                                               3             0                                                                4a            3                                                                5a            34                                                               5b     40                0         72.9 ± 5.4 @                                                                0.5 mM                                      4b            9                                                               18             6                                                               14b            18                                                              14a            13                                                              13             23                                                              15      60                                                                     19a            0                                                               19b            15                                                               8a            41                                                              Mixture of     69                                                              8a and 8b                                                                      Mixture of                                                                             6                                                                      9a and 9b                                                                       6a     5                                                                       6b            85                                                               9a     5                  0% @ 25 μM                                                                           53.7 +/- 3.9                               Mixture of                                                                             13                                                                     6a and 20                                                                      Mixture of                                                                             0.8               14% @ 25 μM                                       6d and 10a                                                                     21a            37                                                              21c            52                                                              21b            45                                                               6c     2                 58.5      68.8 +/- 5.7                                                                   at 0.4 mM                                   6d     0.6               77.7      16.1 +/- 1.1 @                                                                 0.5 mM 30.2 +/                                                                 - 0.9 @ 0.15                                                                   mM                                         17             10                                                               7      50                49.3                                                 10a     7                 77.6      62.4 =/- 2.5 @                                                                 0.2 mM                                     10b     15                68.6                                                 25      0.1                4% @ 10 μM                                                                           26.0 +/- 3.3                               26      2                 31% @ 25 μM                                                                           87.9 +/- 1.5                               27      5                  7% @ 20 μM                                       28      8                 31% @ 20 μM                                       29             88 @ 50 μM                                                   30             96 @ 50 μM                                                   31             41 @ 50 μM                                                   37      3                 0% @ 5 μM                                         38      0.3               11% @ 5 μM                                                                            20.6 +/- 5.7                               40             49 @ 50 μM                                                   41      2                  0% @ 20 μM                                       42      1.5                                                                    43      1.5               16% @ 25 μM                                       48      2                 22% @ 20 μM                                       49      0.15               21% @ 200 μM                                                                         21.2 +/- 2.7                               57             51 @ 50 μM                                                   58             20 @ 50 μM                                                   59      70                                                                     60      9                 59                                                   61      30                175                                                  62      10                                                                     63             90 @ 6 μM                                                    64             100 @ 6 μM                                                   ______________________________________                                          *In vitro Taurocholate Cell Uptake                                             #Unless otherwise noted                                                        =Comparative Example is Example No. 1 in WO 93/16055                     

                  TABLE 6                                                          ______________________________________                                                 TC-uptake TC-uptake                                                                               TC-uptake                                                                             ACAT  ACAT                                           (H14 cells)                                                                              Ileal Loop                                                                              (BBMV) (liver)                                                                              intestine                              Compound                                                                               IC (50)   EC (50)  IC (50)                                                                               IC (50)                                                                              IC (50)                                ______________________________________                                         COMP.   1      μM  74 μM                                                                              3   μM                                                                               20  μM                                                                              20  μM                        EXAMPLE*                                                                       6d      0.6    μM  31 μM                                                                              1.5 μM                                                                               25  μM                                                                              20  μM                        * 38    0.3    μM  12 μM                                                                              2   μM                                                                               15  μM                                                                              N.D.                             49      0.1    μM  12 μM                                                                              N.D.   6   μM                                                                              N.D.                               25      0.1    μM  20 μM                                                                              0.8 μM                                                                               8   μM                                                                              8   μM                        ______________________________________                                          Comparative Example is Example No. 1 in WO 93/16055                      

                  TABLE 7                                                          ______________________________________                                         EFFICACY OF COMPOUND NO. 25 IN CHOLESTEROL-FED                                 HAMSTERS                                                                                               4%                                                                             CHOLES-   0.2%                                         PARAMETER     CONTROL   TYRAMINE  CPD. NO. 25                                  ______________________________________                                         WEIGHT (G)    (mean ± SEM, *p < 0.05, A-Student's t,                                      B-Dunnett's)                                                     day 1         117(2)    114(6)    117(5)                                       day 14        127(3)    127(3)    132(4)                                       LIVER WEIGHT (G)                                                                             5.4(0.3)  4.9(0.4)  5.8(0.2)                                     SER.CHOL(mg %)                                                                               143(7)    119(4)*A,B                                                                               126(2)*A,B                                   HDL-CHOL(mg %)                                                                               89(4)     76(3)*A,B 76(1)*A,B                                    VLDL + LDL    54(7)     42(3)*A   50(3)                                        TGI(mg %)     203(32)   190(15)   175(11)                                      HEPATIC CHOL(mg/g)                                                                           2.5(0.3)  1.9(0.1)*A,B                                                                             1.9(0.1)*A,B                                 HMG COA (pm/mg/min.)                                                                         15.8(7.6) 448.8(21.6)*                                                                             312.9(37.5)*A,                                                       A,B       B                                            7a-OHase (pm/mg/min.)                                                                        235.3(25.1)                                                      24 HR. FECAL Wt (G)     357.2(28.3)*                                                                             291.0(6.0)*A                                 FBA (mM/24 H/100 g)                                                                          2.3(0.1)  A,B       2.4(0.04)                                                  6.2(0.8)  2.7(0.1)*A,B                                                                             11.9(0.5)*A,B                                                        12.3(1.5)*A,                                                                   B                                                      ______________________________________                                    

                  TABLE 8                                                          ______________________________________                                         EFFICACY OF COMPOUND NO. 25 IN RAT                                             ALZET MINIPUMP MODEL                                                                                      20 MPL/DAY                                          PARAMETER        CONTROL   CPD. NO. 25                                         ______________________________________                                         WEIGHT (G)       (mean ± SEM, *p < 0.05,                                                     A-Student's t, B-Dunnett's)                                   day 1            307 (4)   307 (3)                                             day 8            330 (40)  310 (4) *A, B                                       LIVER WEIGHT (G) 15.5 (0.6)                                                                               14.6 (0.4)                                          SER. CHOL (mg %) 85 (3)    84 (3)                                              HEPATIC CHOL (mg/g)                                                                             21 (0.03) 2.0 (0.03)                                          HMG COA pm/mg/min                                                                               75.1 (6.4)                                                                               318.0 (40.7) *A, B                                  7a-OHase (pm/mg/min)                                                                            281.9 (13.9)                                                                             535.2 (35.7) *A, B                                  24 HR. FECAL WT (G)                                                                             5.8 (0.1) 5.7 (0.4)                                           FBA (mM/24H/100 g)                                                                              17.9 (0.9)                                                                               39.1 (4.5) *A, B                                    ______________________________________                                    

Additional in vitro taurocholate uptake tests were conducted in the following compounds listed in Table 9.

                  TABLE 9                                                          ______________________________________                                         Biological Data for Some Compounds of the Present Invention                    Compound    Human TC  Alanine Uptake Percent                                   Number      IC.sub.50 (μM)                                                                        Inhibition @ μM                                       ______________________________________                                          101                  0 @ 1.0                                                   102        0.083                                                               103                  13 @ 0.25                                                 104        0.0056                                                              105        0.6                                                                 106        0.8                                                                 107                  14.0 @ 0.063                                              108        0.3                                                                 109                  2.0 @ 0.063                                               110        0.09                                                                111        2.5                                                                 112        3.0                                                                 113        0.1                                                                 114        0.19                                                                115        8.0                                                                 116        0.3                                                                 117                  12.0 @ 0.625                                              118        0.4                                                                 119        1.3                                                                 120                  34.0 @ 5.0                                                121        0.068                                                               122        1.07                                                                123        1.67                                                                124                  14.0 @ 6.25                                               125        18.0                                                                126                  18 @ 1.25                                                 127        0.55                                                                128        0.7                                                                 129        0.035                                                               131        1.28                                                                132                  5.4 @ 0.063                                               133        16.0                                                                134        0.3                                                                 135        22.0                                                                136        0.09                                                                137        2.4                                                                 138        3.0                                                                 139        >25.0                                                               140                                                                            141                                                                            142        0.5                                                                 143        0.03                                                                144        0.053                                                               262        0.07                                                                263        0.7                                                                 264        0.2                                                                 265        2.0                                                                 266        0.5                                                                 267        0.073                                                               268        0.029                                                               269        0.08                                                                270        0.12                                                                271        0.07                                                                272        0.7                                                                 273        1.9                                                                 274        0.18                                                                275                  5.0 @ 0.25                                                276        0.23                                                                277        0.04                                                                278        3.0                                                                 279        0.4                                                                 280        0.18                                                                281        0.019                                                               282        0.021                                                               283        0.35                                                                284        0.08                                                                285                                                                            286        19.0                                                                287        4.0                                                                 288                  10.0 @ 6.25                                               289        0.23                                                                290        0.054                                                               291        0.6                                                                 292        0.046                                                               293        1.9                                                                 294        0.013                                                               295        1.3                                                                 296        1.6                                                                1000                                                                           1001                                                                           1002                                                                           1003                                                                           1004                                                                           1005        0.0004                                                             1006        0.001                                                              1007        0.001                                                              1008        0.001                                                              1009        0.001                                                              1010        0.001                                                              1011        0.001                                                              1012        0.0015                                                             1013        0.002                                                              1014        0.002                                                              1015        0.002                                                              1016        0.002                                                              1017        0.002                                                              1018        0.002                                                              1019        0.002                                                              1020        0.002                                                              1021        0.002                                                              1022        0.002                                                              1023        0.002                                                              1024        0.002                                                              1025        0.002                                                              1026        0.002                                                              1027        0.002                                                              1028        0.002                                                              1029        0.002                                                              1030        0.002                                                              1031        0.002                                                              1032        0.002                                                              1033        0.002                                                              1034        0.002                                                              1035        0.002                                                              1036        0.002                                                              1037        0.0022                                                             1038        0.0025                                                             1039        0.0026                                                             1040        0.003                                                              1041        0.003                                                              1042        0.003                                                              1043        0.003                                                              1044        0.003                                                              1045        0.003                                                              1046        0.003                                                              1047        0.003                                                              1048        0.003                                                              1049        0.003                                                              1050        0.003                                                              1051        0.003                                                              1052        0.003                                                              1053        0.003                                                              1054        0.003                                                              1055        0.003                                                              1056        0.003                                                              1057        0.003                                                              1058        0.003                                                              1059        0.003                                                              1060        0.0036                                                             1061        0.004                                                              1062        0.004                                                              1063        0.004                                                              1064        0.004                                                              1065        0.004                                                              1066        0.004                                                              1067        0.004                                                              1068        0.004                                                              1069        0.004                                                              1070        0.004                                                              1071        0.004                                                              1072        0.004                                                              1073        0.004                                                              1074        0.004                                                              1075        0.0043                                                             1076        0.0045                                                             1077        0.0045                                                             1078        0.0045                                                             1079        0.005                                                              1080        0.005                                                              1081        0.005                                                              1082        0.005                                                              1083        0.005                                                              1084        0.005                                                              1085        0.005                                                              1086        0.005                                                              1087        0.005                                                              1088        0.0055                                                             1089        0.0057                                                             1090        0.006                                                              1091        0.006                                                              1092        0.006                                                              1093        0.006                                                              1094        0.006                                                              1095        0.006                                                              1096        0.006                                                              1097        0.006                                                              1098        0.006                                                              1099        0.0063                                                             1100        0.0068                                                             1101        0.007                                                              1102        0.007                                                              1103        0.007                                                              1104        0.007                                                              1105        0.007                                                              1106        0.0073                                                             1107        0.0075                                                             1108        0.0075                                                             1109        0.008                                                              1110        0.008                                                              1111        0.008                                                              1112        0.008                                                              1113        0.009                                                              1114        0.009                                                              1115        0.0098                                                             1116        0.0093                                                             1117        0.01                                                               1118        0.01                                                               1119        0.01                                                               1120        0.01                                                               1121        0.01                                                               1122        0.011                                                              1123        0.011                                                              1124        0.011                                                              1125        0.012                                                              1126        0.013                                                              1127        0.013                                                              1128        0.017                                                              1129        0.018                                                              1130        0.018                                                              1131        0.02                                                               1132        0.02                                                               1133        0.02                                                               1134        0.02                                                               1135        0.021                                                              1136        0.021                                                              1137        0.021                                                              1138        0.022                                                              1139        0.022                                                              1140        0.023                                                              1141        0.023                                                              1142        0.024                                                              1143        0.027                                                              1144        0.028                                                              1145        0.029                                                              1146        0.029                                                              1147        0.029                                                              1148        0.03                                                               1149        0.03                                                               1150        0.03                                                               1151        0.031                                                              1152        0.036                                                              1153        0.037                                                              1154        0.037                                                              1155        0.039                                                              1156        0.039                                                              1157        0.04                                                               1158        0.06                                                               1159        0.06                                                               1160        0.062                                                              1161        0.063                                                              1162        0.063                                                              1163        0.09                                                               1164        0.093                                                              1165        0.11                                                               1166        0.11                                                               1167        0.12                                                               1168        0.12                                                               1169        0.12                                                               1170        0.13                                                               1171        0.14                                                               1172        0.14                                                               1173        0.15                                                               1174        0.15                                                               1175        0.17                                                               1176        0.18                                                               1177        0.18                                                               1178        0.19                                                               1179        0.19                                                               1180        0.2                                                                1181        0.22                                                               1182        0.25                                                               1183        0.28                                                               1184        0.28                                                               1185        0.28                                                               1186        0.3                                                                1187        0.32                                                               1188        0.35                                                               1189        0.35                                                               1190        0.55                                                               1191        0.65                                                               1192        1.0                                                                1193        1.0                                                                1194        1.6                                                                1195        1.7                                                                1196        2.0                                                                1197        2.2                                                                1198        2.5                                                                1199        4.0                                                                1200        6.1                                                                1201        8.3                                                                1202        40.0                                                               1203                    0 @ 0.063                                              1204        0.05                                                               1205        0.034                                                              1206        0.035                                                              1207        0.068                                                              1208        0.042                                                              1209                    0 @ 0.063                                              1210        0.14                                                               1211        0.28                                                               1212        0.39                                                               1213        1.7                                                                1214        0.75                                                               1215        0.19                                                               1216        0.39                                                               1217        0.32                                                               1218        0.19                                                               1219        0.34                                                               1220        0.2                                                                1221        0.041                                                              1222        0.065                                                              1223        0.28                                                               1224        0.33                                                               1225        0.12                                                               1226        0.046                                                              1227        0.25                                                               1228        0.038                                                              1229        0.049                                                              1230        0.062                                                              1231        0.075                                                              1232        1.2                                                                1233        0.15                                                               1234        0.067                                                              1235        0.045                                                              1236        0.05                                                               1237        0.07                                                               1238        0.8                                                                1239        0.035                                                              1240        0.016                                                              1241        0.047                                                              1242        0.029                                                              1243        0.63                                                               1244        0.062                                                              1245        0.32                                                               1246        0.018                                                              1247        0.017                                                              1248        0.33                                                               1249        10.2                                                               1250        0.013                                                              1251        0.62                                                               1252        29.                                                                1253        0.3                                                                1254        0.85                                                               1255        0.69                                                               1256        0.011                                                              1257        0.1                                                                1258        0.12                                                               1259        16.5                                                               1260        0.012                                                              1261        0.019                                                              1262        0.03                                                               1263        0.079                                                              1264        0.21                                                               1265        0.24                                                               1266        0.2                                                                1267        0.29                                                               1268        0.035                                                              1269        0.026                                                              1270        0.026                                                              1271        0.011                                                              1272        0.047                                                              1273        0.029                                                              1274        0.028                                                              1275        0.024                                                              1276        0.029                                                              1277        0.018                                                              1278        0.017                                                              1279        0.028                                                              1280        0.76                                                               1281        0.055                                                              1282        0.17                                                               1283        0.17                                                               1284        0.011                                                              1285        0.027                                                              1286        0.068                                                              1287        0.071                                                              1288        0.013                                                              1289        0.026                                                              1290        0.017                                                              1291        0.013                                                              1292        0.025                                                              1293        0.019                                                              1294        0.011                                                              1295        0.014                                                              1296        0.063                                                              1297        0.029                                                              1298        0.018                                                              1299        0.012                                                              1300        1.0                                                                1301        0.15                                                               1302        1.4                                                                1303        0.26                                                               1304        0.25                                                               1305        0.25                                                               1306        1.2                                                                1307        3.1                                                                1308        0.04                                                               1309        0.24                                                               1310        1.16                                                               1311        3.27                                                               1312        5.0                                                                1313        6.1                                                                1314        0.26                                                               1315        1.67                                                               1316        3.9                                                                1317        21.0                                                               1318                                                                           1319                  11.0 @ 0.25                                              1320                                                                           1321                  11.1 @ 5.0                                               1322                   3.0 @ 0.0063                                            1323                   4.0 @ 0.0063                                            1324                  43.0 @ 0.0008                                            1325                   1.0 @ 0.0063                                            1326                  36.0 @ 0.0008                                            1327                   3.0 @ 0.0063                                            1328                  68.0 @ 0.0063                                            1329                   2.0 @ 0.0063                                            1330                   9.0 @ 0.0063                                            1331                  57.0 @ 0.0008                                            1332                  43.0 @ 0.0008                                            1333                    0 @ 0.0063                                             1334                  50.0 @ 0.0008                                            1335                  38.0 @ 0.0008                                            1336                  45.0 @ 0.0008                                            1337                    0 @ 0.0063                                             1338                  1.0 @ 0.25                                               1339                    0 @ 0.063                                              1340                  9.0 @ 0.063                                              1341                  1.0 @ 0.063                                              1342                  1.0 @ 0.063                                              1343                                                                           1344                                                                           1345                  13.0 @ 0.25                                              1346                                                                           1347        0.0036                                                             1348                                                                           1349                                                                           1350                                                                           1351        0.44                                                               1352        0.10                                                               1353        0.0015                                                             1354        0.006                                                              1355        0.0015                                                             1356        0.22                                                               1357        0.023                                                              1358        0.008                                                              1359        0.014                                                              1360        0.003                                                              1361        0.004                                                              1362        0.019                                                              1363        0.008                                                              1364        0.006                                                              1365        0.008                                                              1366        0.015                                                              1367        0.002                                                              1368        0.005                                                              1369        0.005                                                              1370        0.002                                                              1371        0.004                                                              1372        0.004                                                              1373        0.008                                                              1374        0.007                                                              1375        0.002                                                              1449        0.052                                                              1450        0.039                                                              1451        0.014                                                              ______________________________________                                    

Additional in vitro taurocholate uptake tests and in vivo rat gavage tests were conducted on the following compounds listed in Tables 10 and 11.

                  TABLE 10                                                         ______________________________________                                         In Vitro Taurocholate Uptake Assay Data for Some                               Additional Compounds of the Present Invention                                  Compound of Example Number                                                                       Human TC IC50 (nM)                                           ______________________________________                                         1402              25                                                           1403              23                                                           1404              10                                                           1405              21                                                           1406              4                                                            1407              3                                                            1408              1                                                            1409              0.9                                                          1410              2                                                            1411              2                                                            1412              3                                                            1413              3                                                            1414              15                                                           1415              2                                                            1416              14                                                           1417              2                                                            1418              <1                                                           1419              3                                                            1420              11                                                           1421              4                                                            1422              3                                                            1423              3                                                            1424              14                                                           1425              2                                                            1426              0.3                                                          1427              2                                                            1428              0.7                                                          1429                                                                           1430              3                                                            1431              5                                                            1432              26                                                           1433              67                                                           ______________________________________                                    

                  TABLE 11                                                         ______________________________________                                         Rat Gavage Assay Data for Some Additional Compounds                            of the Present Invention                                                       Compound of        Dose       Delta (micromoles fecal                          Example No.                                                                             Study No. (mg/kg/day)                                                                               bile acid per day)                               ______________________________________                                         1402     28        5          58.2                                                                .2         1.3                                                                 .04        0.3                                              1402     30        2          50.3                                                                .4         40.9                                                                .08        48.5                                                                .016       22.9                                             1403     30        2          41.6                                                                .4         35.2                                                                .08        11.9                                                                .016       3                                                1404     28        5          93.7                                                                .2         59.1                                                                .04        33.5                                             1406     32        2          47.8                                                                .4         31.6                                                                .08        12.8                                                                .016       -8.5                                             1407     32        2          51.9                                                                .4         30.1                                                                .08        27.5                                                                .016       6.4                                              1407     33        2          35                                                                  .4         12.7                                                                .08        -.04                                                                .016       -4.5                                             1408     29        2          41.2                                                                .4         36.8                                                                .08        16.8                                                                .016       -3.3                                             1408     37        2          26.2                                                                .4         45.2                                                                .08        26.3                                                                .016       6.6                                              1409     33        2          19.2                                                                .4         28.7                                                                .08        14.1                                                                .016       -1.7                                             1409     41        2          44.2                                                                .4         35.9                                                                .08        14.5                                                                .016       11                                               1410     33        32.4                                                                           34.3                                                                           27.9                                                                           9.3                                                         1410     35        2          26.2                                                                .4         36.5                                                                .08        18.5                                                                .016       20.4                                             1411     34        2          63.4                                                                .4         54.1                                                                .08        33                                                                  .016       22.3                                             1413     26        5          52.3                                                                .2         42.4                                                                .04        19                                               1414     27        5          45.2                                                                .2         39.5                                                                .04        14.3                                             1414     31        2          41.5                                                                .4         33.7                                                                .08        29                                                                  .016       3.8                                              1415     28        5          59.9                                                                .2         48.1                                                                .04        23.9                                             1415     37        2          48.9                                                                .4         25.7                                                                .08        27.1                                                                .016       12.7                                             1416     29        2          46.1                                                                .4         21.9                                                                .08        25                                                                  .016       -7.8                                             1417     31        2          51.4                                                                .4         42                                                                  .08        39.6                                                                .016       29.3                                             1418     29        2          20.3                                                                .4         29.5                                                                .08        -4.6                                                                .016       -10                                              1419     31        2          28.5                                                                .4         13.9                                                                .08        10.3                                                                .016       5.8                                              1420     31        2          53.1                                                                .4         45                                                                  .08        38.1                                                                .016       29.6                                             1421     32        2          57.8                                                                .4         27.7                                                                .08        25.3                                                                .016       4.7                                              1423     34        2          56.5                                                                .4         69.3                                                                .08        35.3                                                                .016       14.4                                             1425     21        5          91.8                                                                .2         100.                                                                .04        66.4                                             1425     30        2          44.6                                                                .4         62                                                                  .08        69.5                                                                .016       31.6                                             1425     40        2          48.3                                                                .4         45                                                                  .08        31.2                                                                .016       30                                               1426     33        2          52.4                                                                .4         19.5                                                                .08        23.1                                                                .016       24.6                                             1426     35        2          37.7                                                                .4         41.7                                                                .08        40.5                                                                .016       24.6                                             1426     39        2          54.3                                                                .4         48.7                                                                .08        51.8                                                                .016       26.8                                             1426     43        2          40.8                                                                .4         21.7                                                                .08        5.9                                                                 .016       4.1                                              1427     40        2          36.7                                                                .4         35.8                                                                .08        27.3                                                                .016       13.8                                             1428     34        2          40.4                                                                .4         64.9                                                                .08        24.4                                                                .016       12.2                                             1428     42        2          46                                                                  .4         40.7                                                                .08        26                                                                  .016       1.1                                              1429     41        2          34.5                                                                .4         24.9                                                                .08        18.7                                                                .016       9.2                                              1429     42        2          47.1                                                                .4         31.1                                                                .08        35.5                                                                .016       4.8                                              1430     30        2          51.2                                                                .4         50.4                                                                .08        20.7                                                                .016       -5.6                                             1431     32        28.3                                                                           45.8                                                                           21.9                                                                           1.1                                                         1432     28        5          36.2                                                                .2         9.7                                                                 .04        2.7                                              1433     24        20         66.5                                                                2          47.4                                                                .2         26.5                                             ______________________________________                                    

The examples herein can be repeated with similar success by substituting the generically or specifically described reactants and/or operating conditions of this invention for those used in the preceding examples.

Novel compositions of the invention are further illustrated in attached Exhibits A and B.

The invention being thus described, it is apparent that the same can be varied in many ways. Such variations are not to be regarded as a departure from the spirit and scope of the present invention, and all such modifications and equivalents as would be obvious to one skilled in the art are intended to be included within the scope of the following claims.

                  TABLE C2                                                         ______________________________________                                         Exhibit A                                                                      Alternative Compounds #2 (Families F101-F123)                                   ##STR540##                                                                          Cpd                                                                      Family                                                                               #      R.sup.1 ═R.sup.2                                                                    R.sup.5         (R.sup.x)q                               ______________________________________                                         F101         CHOSEN   Ph-             CHOSEN                                                FROM                     FROM                                                  TABLE 1                  TABLE 1                                  F102         CHOSEN   p-F-Ph-         CHOSEN                                                FROM                     FROM                                                  TABLE 1                  TABLE 1                                  F103         CHOSEN   m-F-Ph-         CHOSEN                                                FROM                     FROM                                                  TABLE 1                  TABLE 1                                  F104         CHOSEN   p-CH.sub.3 O-Ph-                                                                               CHOSEN                                                FROM                     FROM                                                  TABLE 1                  TABLE 1                                  F105         CHOSEN   m-CH.sub.3 O-Ph-                                                                               CHOSEN                                                FROM                     FROM                                                  TABLE 1                  TABLE 1                                  F106         CHOSEN   p-(CH.sub.3).sub.2 N-Ph-                                                                       CHOSEN                                                FROM                     FROM                                                  TABLE 1                  TABLE 1                                  F107         CHOSEN   m-(CH.sub.3).sub.2 N-Ph                                                                        CHOSEN                                                FROM                     FROM                                                  TABLE 1                  TABLE 1                                  F108         CHOSEN   I.sup.-, p-(CH.sub.3).sub.3 --N.sup.+ -Ph-                                                     CHOSEN                                                FROM                     FROM                                                  TABLE 1                  TABLE 1                                  F109         CHOSEN   I.sup.-, m-(CH.sub.3).sub.3 --N.sup.+ -Ph-                                                     CHOSEN                                                FROM                     FROM                                                  TABLE 1                  TABLE 1                                  F110         CHOSEN   I.sup.-, p-(CH.sub.3).sub.3 --N.sup.+ --CH.sub.2                               CH.sub.2 --     CHOSEN                                                FROM     (OCH.sub.2 CH.sub.2).sub.2 --O-Ph-                                                             FROM                                                  TABLE 1                  TABLE 1                                  F111         CHOSEN   I.sup.-, m-(CH.sub.3).sub.3 --N.sup.+ --CH.sub.2                               CH.sub.2 --     CHOSEN                                                FROM     (OCH.sub.2 CH.sub.2).sub.2 --O-Ph-                                                             FROM                                                  TABLE 1                  TABLE 1                                  F112         CHOSEN   I.sup.-, p-(N,N-                                                                               CHOSEN                                                FROM     dimethylpiperazine)-(N')-                                                                      FROM                                                  TABLE 1  CH.sub.2 --(OCH.sub.2 CH.sub.2).sub.2 --O-Ph-                                                  TABLE 1                                  F113         CHOSEN   I.sup.-, m-(N,N-                                                                               CHOSEN                                                FROM     dimethylpiperazine)-(N')-                                                                      FROM                                                  TABLE 1  CH.sub.2 --(OCH.sub.2 CH.sub.2).sub.2 --O-Ph-                                                  TABLE 1                                  F114         CHOSEN   m-F-Ph-         CHOSEN                                                FROM     p-CH.sub.3 O--  FROM                                                  TABLE 1                  TABLE 1                                  F115         CHOSEN   3,4,dioxy-methylene-Ph-                                                                        CHOSEN                                                FROM                     FROM                                                  TABLE 1                  TABLE 1                                  F116         CHOSEN   m-F-Ph-         CHOSEN                                                FROM     p-F-Ph-         FROM                                                  TABLE 1                  TABLE 1                                  F117         CHOSEN   m-CH.sub.3 O--  CHOSEN                                                FROM     p-F-Ph-         FROM                                                  TABLE 1                  TABLE 1                                  F118         CHOSEN   4-pyridine      CHOSEN                                                FROM                     FROM                                                  TABLE 1                  TABLE 1                                  F119         CHOSEN   N-methyl-4-pyridinium                                                                          CHOSEN                                                FROM                     FROM                                                  TABLE 1                  TABLE 1                                  F120         CHOSEN   3-pyridine      CHOSEN                                                FROM                     FROM                                                  TABLE 1                  TABLE 1                                  F121         CHOSEN   N-methyl-3-pyridinium                                                                          CHOSEN                                                FROM                     FROM                                                  TABLE 1                  TABLE 1                                  F122         CHOSEN   2-pyridine      CHOSEN                                                FROM                     FROM                                                  TABLE 1                  TABLE 1                                  F123         CHOSEN   p-CH.sub.3 O.sub.2 C-Ph-                                                                       CHOSEN                                                FROM                     FROM                                                  TABLE 1                  TABLE 1                                  ______________________________________                                    

Similar families can be generated where R¹ is not equal to R², such as R¹ =Et and R² =n-Bu, but (R^(x))q is chosen from table C1. ##STR541## 

What is claimed is:
 1. A compound of formula (I): wherein:q is an integer from 1 to 4; n is 2; R¹ and R² are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, haloalkyl, alkylaryl, arylalkyl, alkoxy, alkoxyalkyl, dialkylamino, alkylthio, (polyalkyl)aryl, and cycloalkyl, wherein alkyl, alkenyl, alkynyl, haloalkyl, alkylaryl, arylalkyl, alkoxy, alkoxyalkyl, dialkylamino, alkylthio, (polyalkyl)aryl, and cycloalkyl optionally are substituted with one or more substituents selected from the group consisting of OR⁹, NR⁹ R¹⁰, N⁺ R⁹ R¹⁰ R^(w) A⁻, SR⁹, SR⁺ R⁹ R¹⁰ A⁻. P⁺ R⁹ R¹⁰ R¹¹ A⁻, S(O)R⁹, SO₂ R⁹, SO₃ R⁹, CO₂ R⁹, CN, halogen, oxo, and CONR⁹ R¹⁰, wherein alkyl, alkenyl, alkynyl, alkylaryl, alkoxy, alkoxyalkyl, (polyalkyl)aryl, and cycloalkyl optionally have one or more carbons replaced by O, NR⁹, N⁺ R⁹ R¹⁰ A-, S, SO, SO₂, S⁺ R⁹ A⁻, P⁺ R⁹ R¹⁰ A⁻, or phenylene, wherein R⁹, R¹⁰, and R^(w) are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, acyl, heterocycle, ammoniumalkyl, arylalkyl, and alkylammoniumalkyl; or R¹ and R² taken together with the carbon to which they are attached form C₃ -C₁₀ cycloalkyl; R³ and R⁴ are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, acyloxy, aryl, heterocycle, OR⁹, NR⁹ R¹⁰, SR⁹, S(O)R⁹, SO₂ R⁹, and SO₃ R⁹, wherein R⁹ and R¹⁰ are as defined above; or R³ and R⁴ together form ═O, ═NOR¹¹, ═S, ═NNR¹¹ R¹², ═NR⁹, or ═CR¹¹ R¹², wherein R¹¹ and R¹² are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkenylalkyl, alkynylalkyl, heterocycle, carboxyalkyl, carboalkoxyalkyl, cycloalkyl, cyanoalkyl, OR⁹, NR⁹ R¹⁰, SR⁹, S(O)R⁹, SO₂ R⁹, SO₃ R⁹, CO₂ R⁹, CN, halogen, oxo, and CONR⁹ R¹⁰, wherein R⁹ and R¹⁰ are as defined above, provided that both R³ and R⁴ cannot be OH, NH₂, and SH, or R¹¹ and R¹² together with the nitrogen or carbon atom to which they are attached form a cyclic ring; R⁵ is substituted aryl, wherein aryl is substituted with one or more substituent groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle, arylalkyl, quaternary heterocycle, quaternary heteroaryl, halogen, oxo, OR¹³, NR¹³ R¹⁴, SR¹³, S(O)R¹³, SO₂ R¹³, SO₃ R¹³, NR¹³ OR¹⁴, NR¹³ NR¹⁴ R¹⁵, NO₂, CO₂ R¹³, CN, OM, SO₂ OM, SO₂ NR¹³ R¹⁴, C(O)NR¹³ R¹⁴, C(O)OM, COR¹³, P(O)R¹³ R¹⁴, P⁺ R¹³ R¹⁴ R¹⁵ A⁻, P(OR¹³)OR¹⁴, S⁺ R¹³ R¹⁴ A⁻, and N⁺ R⁹ R¹¹ R¹² A⁻, wherein:A⁻ is a pharmaceutically acceptable anion and M is a pharmaceutically acceptable cation, said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, and heterocycle can be further substituted with one or more substituent groups selected from the group consisting of OR⁷, NR⁷ R⁸, SR⁷, S(O)R⁷, SO₂ R⁷, SO₃ R⁷, CO₂ R⁷, CN, oxo, CONR⁷ R⁸, N⁺ R⁷ R⁸ R⁹ A-, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, arylalkyl, quaternary heterocycle, quaternary heteroaryl, P(O)R⁷ R⁸, P⁺ R⁷ R⁸ R⁹ A⁻, and P(O)(OR⁷)OR⁸, and wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, and heterocycle can optionally have one or more carbons replaced by O, NR⁷, N⁺ R⁷ R⁸ A-, S, SO, SO₂, S⁺ R⁷ A-, PR⁷, P(O)R⁷, P⁺ R⁷ R⁸ A-, or phenylene, and R¹³, R¹⁴, and R¹⁵ are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, polyalkyl, aryl, arylalkyl, cycloalkyl, heterocycle, heteroaryl, quaternary heterocycle, quaternary heteroaryl, and quaternary heteroarylalkyl, wherein alkyl, alkenyl, alkynyl, arylalkyl, heterocycle, and polyalkyl optionally have one or more carbons replaced by O, NR⁹, N⁺ R⁹ R¹⁰ A-, S, SO, SO₂, S⁺ R⁹ A⁻, PR⁹, P⁺ R⁹ R¹⁰ A-, P(O)R⁹, phenylene, carbohydrate, amino acid, peptide, or polypeptide, and R¹³, R¹⁴, and R¹⁵ are optionally substituted with one or more groups selected from the group consisting of sulfoalkyl, quaternary heterocycle, quaternary heteroaryl, OR⁹, NR⁹ R¹⁰, N⁺ R⁹ R¹¹ R¹² A⁻, SR⁹, S(O)R⁹, SO₂ R⁹, SO₃ R⁹, oxo, CO₂ R⁹, CN, halogen, CONR⁹ R¹⁰, SO₂ OM, SO₂ NR⁹ R¹⁰, PO(OR¹⁶)OR¹⁷, P⁺ R⁹ R¹⁰ R¹¹ A-, S⁺ R⁹ R¹⁰ A-, and C(O)OM, wherein R¹⁶ and R¹⁷ are independently selected from the substituents constituting R⁹ and M; or R¹⁴ and R¹⁵, together with the nitrogen atom to which they are attached, form a cyclic ring; and R⁶ is hydrogen; R⁷ and R⁸ are independently selected from the group consisting of hydrogen and alkyl; and one or more R^(x) are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, polyalkyl, acyloxy, aryl, arylalkyl, halogen, haloalkyl, cycloalkyl, heterocycle, heteroaryl, polyether, quaternary heterocycle, quaternary heteroaryl, OR¹³, NR¹³ R¹⁴, SR¹³, S(O)R¹³, S(O)₂ R¹³, SO₃ R¹³, S⁺ R¹³ R¹⁴ A-, NR¹³ OR¹⁴, NR¹³ NR¹⁴ R¹⁵, NO₂, CO₂ R¹³, CN, OM, SO₂ OM, SO₂ NR¹³ R¹⁴, NR¹⁴ C(O)R¹³, C(O)NR¹³ R¹⁴, NR14C(O)R13, C(O)OM, COR¹³, OR¹⁸, S(O)_(n) NR¹⁸, NR¹³ R¹⁸, NR¹⁸ OR¹⁴, N⁺ R⁹ R¹¹ R¹² A⁻, P⁺ R⁹ R¹¹ R¹² A⁻, amino acid, peptide, polypeptide, and carbohydrate, wherein alkyl, alkenyl, alkynyl, cycloalkyl, aryl, polyalkyl, heterocycle, acyloxy, arylalkyl, haloalkyl, polyether, quaternary heterocycle, and quaternary heteroaryl can be further substituted with OR⁹, NR⁹ R¹⁰, N⁺ R⁹ R¹¹ R¹² A⁻, SR⁹, S(O)R⁹, SO₂ R⁹, SO₃ R⁹, oxo, CO₂ R⁹, CN, halogen, CONR⁹ R¹⁰, SO₂ OM, SO₂ NR⁹ R¹⁰, PO(OR¹⁶)OR¹⁷, P⁺ R⁹ R¹¹ R¹² A⁻, S⁺ R⁹ R¹⁰ A⁻, or C(O)OM, and wherein R¹⁸ is selected from the group consisting of acyl, arylalkoxycarbonyl, arylalkyl, heterocycle, heteroaryl, alkyl, wherein acyl, arylalkoxycarbonyl, arylalkyl, heterocycle, heteroaryl, alkyl, quaternary heterocycle, and quaternary heteroaryl optionally are substituted with one or more substituents selected from the group consisting of OR⁹, NR⁹ R¹⁰, N⁺ R⁹ R¹¹ R¹² A⁻, SR⁹, S(O)R⁹, SO₂ R⁹, SO₃ R⁹, oxo, CO₂ R⁹, CN, halogen, CONR⁹ R¹⁰, SO₃ R⁹, SO₂ OM, SO₂ NR⁹ R¹⁰, PO(OR¹⁶)OR¹⁷, and C(O)OM, wherein in R^(x), one or more carbons are optionally replaced by O, NR¹³, N⁺ R¹³ R¹⁴ A-, S, SO, SO₂, S⁺ R¹³ A⁻, PR¹³, P(O)R¹³, P⁺ R¹³ R¹⁴ A-, phenylene, amino acid, peptide, polypeptide, carbohydrate, polyether, or polyalkyl, wherein in said polyalkyl, phenylene, amino acid, peptide, polypeptide, and carbohydrate, one or more carbons are optionally replaced by O, NR⁹, N⁺ R⁹ R¹⁰ A⁻, S, SO, SO₂, S⁺ R⁹ A-, PR⁹, P⁺ R⁹ R¹⁰ A-, or P(O)R⁹ ; wherein quaternary heterocycle and quaternary heteroaryl are optionally substituted with one or more groups selected from the group consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle, arylalkyl, halogen, oxo, OR¹³, NR¹³ R¹⁴, SR¹³, S(O)R¹³, SO₂ R¹³, SO₃ R¹³, NR¹³ OR¹⁴, NR¹³ NR¹⁴ R¹⁵, NO₂, CO₂ R¹³, CN, OM, SO₂ OM, SO₂ NR¹³ R¹⁴, C(O)NR¹³ R¹⁴, C(O)OM, COR¹³, P(O)R¹³ R¹⁴, P⁺ R¹³ R¹⁴ R¹⁵ A⁻, P(OR¹³)OR¹⁴, S⁺ R¹³ R¹⁴ A⁻, and N⁺ R⁹ R¹¹ R¹² A⁻, provided that when R⁵ or R⁶ is phenyl, only one of R¹ or R² is H; provided that when q=1 and R^(x) is styryl, anilido, or anilinocarbonyl, only one of R⁵ or R⁶ is alkyl; or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
 2. A compound of claim 1 having the structural formula: ##STR542## wherein Me is methyl and Bu is butyl.
 3. A compound of claim 1 having the structural formula: ##STR543## wherein Me is methyl and Bu is butyl.
 4. A compound of claim 1 having the structural formula: ##STR544## wherein Me is methyl and Bu is butyl.
 5. A compound of claim 1 having the structural formula: ##STR545## wherein Me is methyl and Bu is butyl.
 6. A compound of claim 1 having the structural formula: ##STR546## wherein Me is methyl and Bu is butyl.
 7. A compound of claim 1 having the structural formula: ##STR547## wherein Me is methyl and Bu is butyl.
 8. A compound of claim 1 having the structural formula: ##STR548## wherein Me is methyl and Bu is butyl.
 9. A compound of claim 1 having the structural formula: ##STR549## wherein Me is methyl and Bu is butyl.
 10. A compound of claim 1 having the structural formula: ##STR550## wherein Me is methyl and Bu is butyl.
 11. A compound of claim 1 having the structural formula: ##STR551## wherein Et is ethyl.
 12. A compound of claim 1 having the structural formula: ##STR552## wherein Me is methyl and Bu is butyl.
 13. A compound of claim 1 having the structural formula: ##STR553## wherein Me is methyl and Bu is butyl.
 14. A compound of claim 1 having the structural formula: ##STR554## wherein Me is methyl and Bu is butyl.
 15. A compound of formula (I): ##STR555## wherein: q is an integer from 1 to 4;n is 2; R¹ and R² are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, haloalkyl, alkylaryl, arylalkyl, alkoxy, alkoxyalkyl, dialkylamino, alkylthio, (polyalkyl)aryl, and cycloalkyl, wherein alkyl, alkenyl, alkynyl, haloalkyl, alkylaryl, arylalkyl, alkoxy, alkoxyalkyl, dialkylamino, alkylthio, (polyalkyl)aryl, and cycloalkyl optionally are substituted with one or more substituents selected from the group consisting of OR⁹, NR⁹ R¹⁰, N⁺ R⁹ R¹⁰ R^(w) A⁻, SR⁹, S⁺ R⁹ R¹⁰ A⁻. P⁺ R⁹ R¹⁰ R¹¹ A⁻, S(O)R⁹, SO₂ R⁹, SO₃ R⁹, CO₂ R⁹, CN, halogen, oxo, and CONR⁹ R¹⁰, wherein alkyl, alkenyl, alkynyl, alkylaryl, alkoxy, alkoxyalkyl, (polyalkyl)aryl, and cycloalkyl optionally have one or more carbons replaced by O, NR⁹, N⁺ R⁹ R¹⁰ A-, S, SO, SO₂, S⁺ R⁹ A⁻, P⁺ R⁹ R¹⁰ A⁻, or phenylene, wherein R⁹, R¹⁰, and R^(w) are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, acyl, heterocycle, ammoniumalkyl, arylalkyl, carboxyalkyl, carboxyheteroaryl, carboxyheterocycle, carboalkoxyalkyl, carboxyalkylamino, heteroarylalkyl, heterocyclylalkyl, and alkylammoniumalkyl; or R¹ and R² taken together with the carbon to which they are attached form C₃ -C₁₀ cycloalkyl; R³ and R⁴ are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, acyloxy, aryl, heterocycle, OR⁹, NR⁹ R¹⁰, SR⁹, S(O)R⁹, SO₂ R⁹, and SO₃ R⁹, wherein R⁹ and R¹⁰ are as defined above; or R³ and R⁴ together form ═O, ═NOR¹¹, ═S, ═NNR¹¹ R¹², ═NR⁹, or ═CR¹¹ R¹², wherein R¹¹ and R¹² are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkenylalkyl, alkynylalkyl, heterocycle, carboxyalkyl, carboalkoxyalkyl, cycloalkyl, cyanoalkyl, OR⁹, NR⁹ R¹⁰, SR⁹, S(O)R⁹, SO₂ R⁹, SO₃ R⁹, CO₂ R⁹, CN, halogen, oxo, and CONR⁹ R¹⁰, wherein R⁹ and R¹⁰ are as defined above, provided that both R³ and R⁴ cannot be OH, NH₂, and SH, or R¹¹ and R¹² together with the nitrogen or carbon atom to which they are attached form a cyclic ring; R⁵ is aryl substituted with one or more substituent groups independently selected from the group consisting of NR¹³ C(O)R¹⁴, NR¹³ C(O)NR¹⁴ R¹⁵, NR¹³ CO₂ R¹⁴, OC(O)R¹³, OC(O)NR¹³ R¹⁴, NR¹³ SOR¹⁴, NR¹³ SOR¹⁴, NR¹³ SO₂ R¹⁴, NR¹³ SONR¹⁴ R¹⁵, and NR¹³ SO₂ NR¹⁴ R¹⁵, wherein:R¹³, R¹⁴, and R¹⁵ are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, arylalkyl, alkylarylalkyl, alkylheteroarylalkyl, alkylheterocyclylalkyl, cycloalkyl, heterocycle, heteroaryl, quaternary heterocycle, quaternary heteroaryl, heterocyclylalkyl, heteroarylalkyl, quaternary heterocyclylalkyl, quaternary heteroarylalkyl, alkylammoniumalkyl, and carboxyalkylaminocarbonylalkyl, R¹³, R¹⁴, and R¹⁵ are optionally substituted with one or more groups selected from the group consisting of hydroxy, amino, sulfo, carboxy, alkyl, carboxyalkyl, heterocycle, heteroaryl, sulfoalkyl, quaternary heterocycle, quaternary heteroaryl, quaternary heterocyclylalkyl, quaternary heteroarylalkyl, guanidinyl, OR⁹, NR⁹ R¹⁰, N⁺ R⁹ R¹¹ R¹² A⁻, SR⁹, S(O)R⁹, SO₂ R⁹, SO₃ R⁹, oxo, CO₂ R⁹, CN, halogen, CONR⁹ R¹⁰, SO₂ OM, SO₂ NR⁹ R¹⁰, PO(OR¹⁶)OR¹⁷, P⁺ R⁹ R¹⁰ R¹¹ A-, S⁺ R⁹ R¹⁰ A-, and C(O)OM, wherein A⁻ is an pharmaceutically acceptable anion and M is a pharmaceutically acceptable cation, wherein R¹⁶ and R¹⁷ are independently selected from the substituents constituting R⁹ and M; or R¹³ and R¹⁴, together with the nitrogen atom to which they are attached form a mono- or polycyclic heterocycle that is optionally substituted with one or more radicals selected from the group consisting of oxo, carboxy and quaternary salts; or R¹⁴ and R¹⁵, together with the nitrogen atom to which they are attached, form a cyclic ring; and R⁶ is hydrogen; R⁷ and R⁸ are independently selected from the group consisting of hydrogen and alkyl; and one or more R^(x) are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, polyalkyl, acyloxy, aryl, arylalkyl, halogen, haloalkyl, cycloalkyl, heterocycle, heteroaryl, polyether, quaternary heterocycle, quaternary heteroaryl, OR¹³, NR¹³ R¹⁴, SR¹³, S(O)R¹³, S(O)₂ R¹³, SO₃ R¹³, S⁺ R¹³ R¹⁴ A-, NR¹³ OR¹⁴, NR¹³ NR¹⁴ R¹⁵, NO₂, CO₂ R¹³, CN, OM, SO₂ OM, SO₂ NR¹³ R¹⁴, NR¹⁴ C(O)R¹³, C(O)NR¹³ R¹⁴, NR14C(O)R13, C(O)OM, COR¹³, OR¹⁸, S(O)_(n) NR¹⁸, NR¹³ R¹⁸, NR¹⁸ OR¹⁴, N⁺ R⁹ R¹¹ R¹² A⁻, P⁺ R⁹ R¹¹ R¹² A⁻, amino acid, peptide, polypeptide, and carbohydrate, wherein alkyl, alkenyl, alkynyl, cycloalkyl, aryl, polyalkyl, heterocycle, acyloxy, arylalkyl, haloalkyl, polyether, quaternary heterocycle, and quaternary heteroaryl can be further substituted with OR⁹, NR⁹ R¹⁰, N⁺ R⁹ R¹¹ R¹² A⁻, SR⁹, S(O)R⁹, SO₂ R⁹, SO₃ R⁹, oxo, CO₂ R⁹, CN, halogen, CONR⁹ R¹⁰, SO₂ OM, SO₂ NR⁹ R¹⁰, PO(OR¹⁶)OR¹⁷, P⁺ R⁹ R¹¹ R¹² A⁻, S⁺ R⁹ R¹⁰ A⁻, or C(O)OM, and wherein R¹⁸ is selected from the group consisting of acyl, arylalkoxycarbonyl, arylalkyl, heterocycle, heteroaryl, alkyl, wherein acyl, arylalkoxycarbonyl, arylalkyl, heterocycle, heteroaryl, alkyl, quaternary heterocycle, and quaternary heteroaryl optionally are substituted with one or more substituents selected from the group consisting of OR⁹, NR⁹ R¹⁰, N⁺ R⁹ R¹¹ R¹² A⁻, SR⁹, S(O)R⁹, SO₂ R⁹, SO₃ R⁹, oxo, CO₂ R⁹, CN, halogen, CONR⁹ R¹⁰, SO₃ R⁹, SO₂ OM, SO₂ NR⁹ R¹⁰, PO(OR¹⁶)OR¹⁷, and C(O)OM, wherein in R^(x), one or more carbons are optionally replaced by O, NR¹³, N⁺ R¹³ R¹⁴ A-, S, SO, SO₂, S⁺ R¹³ A⁻, PR¹³, P(O)R¹³, P⁺ R¹³ R¹⁴ A-, phenylene, amino acid, peptide, polypeptide, carbohydrate, polyether, or polyalkyl, wherein in said polyalkyl, phenylene, amino acid, peptide, polypeptide, and carbohydrate, one or more carbons are optionally replaced by O, NR⁹, N⁺ R⁹ R¹⁰ A⁻, S, SO, SO₂, S⁺ R⁹ A-, PR⁹, P⁺ R⁹ R¹⁰ A-, or P(O)R⁹ ; wherein quaternary heterocycle and quaternary heteroaryl are optionally substituted with one or more groups selected from the group consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle, arylalkyl, halogen, oxo, OR¹³, NR¹³ R¹⁴, SR¹³, S(O)R¹³, SO₂ R¹³, SO₃ R¹³, NR¹³ OR¹⁴, NR¹³ NR¹⁴ R¹⁵, NO₂, CO₂ R¹³, CN, OM, SO₂ OM, SO₂ NR¹³ R¹⁴, C(O)NR¹³ R¹⁴, C(O)OM, COR¹³, P(O)R¹³ R¹⁴, P⁺ R¹³ R¹⁴ R¹⁵ A⁻, P(OR¹³)OR¹⁴, S⁺ R¹³ R¹⁴ A⁻, and N⁺ R⁹ R¹¹ R¹² A⁻, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
 16. A compound of claim 15 having the structural formula: ##STR556## wherein Me is methyl and Bu is butyl.
 17. A compound of claim 15 having the structural formula: ##STR557## wherein Me is methyl and Bu is butyl.
 18. A compound of claim 15 having the structural formula: ##STR558## wherein Me is methyl and Bu is butyl.
 19. A compound of claim 15 having the structural formula: ##STR559## 